1-carboxymethylene-2-(allyl-substituted)-2, 4b-dimethyl-4-hydroxydodecahydrophenanthrene and process



United States Patent ice DELCAHYDROPHENANTHRENE ANnrRocESs No-Drawing. Application December 31,1956 senai'Noa-6s1,4ss a 4 Claims C1. 260 3409) This invention is concerned generally with dimethylcyclopentanopolyhydrophenanthrene compounds and with processes for preparing them. More particularly, it relates to agnovel process for preparing A"{*-3,11,20-triketopregnene; starting with l-alkoxyethinyl lhydroxy-Z-methally1-2,4b-dimethyl-4;keto -1,2,3,4,4a,4b,5,6,78,10,1 0a-d0- decahydrophenanthrene compounds havingiin the 7-positioula ketaltor other substituent-acomtertible to' keto. by hydrolysis, to the individual steps in this process, and t0 the intermediate compounds-thus obtained.

This application is a continuation-impart of our co pending application Serial'rNb. 310,133 filed September 17, 1952, now abandoned. Th A -triketo:pregnene, which -is ,valuable an intermediate in thepreparationof--steroid hormones such as cortisone, may be chemically represented as follows:

wherein R is alkyl, and X may be 2 I 0 ey \Qand being hydrocarbon radicals,= L and'M being ihyd,rophenanthrene (Compound 7).

oxygen or sulfur, and Z,being alkylene. In eac'hi-ofthe process operations utilizefdqby uslintpreparing A -3 ,11,2;0--. triketo-pregnene, the keto groi1p in ring A is Blocked with a ketal or cyclic-ketal protecting group. At any stage in l 4 the process,'this keto group may be regenerated by acid iricl-usles.v

hydrolysis whereby h mketal,suhsti uent,.uhie

the simple ketals, thioketal's, hemithio ketals, cyclic keta ls 1. enedioxy 1 ,2,3,4,4a,4b;5,6 ,7,8,10,10a dodecahydrophenanthrene (Compound 5); the latter compound is 2,887,493 Patented ;May 19, 1.959

grouping, cyclic rthioketals and cyclic hemithioketals, is hydrolyzed and, atvthe. same time, the vdouble bond shifts from .ring ,B to ring 'A ,thus forming 4a e s-unsaturated ketone. We ordinarily prefer to utilize an .ethylene-diQXY substituent as the protecting group, ,and our preferred starting ,material is therefore .1 -alkoxyethinyl-l-hydroxy- 2-methallyl-2,4 b dimethyl-4-keto-7 -.ethylenedioxyt- 1,2,3, '4,'4a,-4b,5,6,7,8,10,10a dOdecahydrophenanthIene.

Utilizing the latter compound as, startingmater'ial, ,and inaccordance with our presently invented lprocess, ,1-,alkony'ethinyl L-hydroxy -.2 -,methall yl-2,4b-dimethyl-4- keto 7 -ethylenedioxy 1;2,3,4l,4a,-4b,5,6,,7,8,1Q,10a do- .,decahydrophenant-hrene L (Compound .1 yhereinheloiv) is. re acted with a dilute aqueous mineral acid solution to produce the corresponding 1-carboalkoxymethylene-Z-methallyl-2,4,b;-dimethyl-4-keto-7-ethylenedioxy 1,2,3,4,4a,4b, 5,6,7,8,I0,lOa-dodecahydrophenanthrene (Compound 2); the-latter compound is reacted with an alkaline saponifying agent thereby forming 1-carboxymethylene-2-methallyl-2,4b-dimethyl4-keto-7-ethylenedioxy 1,2,3,4,4a,4b, 5,6,7,8,10,10a-dqdecahydrophenanthrene (Compound 3). The "1L:carboxymethylene-2-methallyl 2,4b-dimethyl-4- keto 7 -.-e'thylenedioxy -1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthreneflier-then reacted with an alkali metal in a lower alkanokor in liquid ammonia to produce 1-carboxymethyl=2-methallyl 2,4b dimethyl 4 hydroxy-7 ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,1021 do- Aecahydrophenanthrene (Compound 4). Alternatively, this reduction; operation, which involves the reduction of both th.e C4keto group to hydroxy and the l-carboxymethylene radical to a carboxymethyl grouping, can be carried-out step-wise by reacting the l-carboxymethylene Z-methallyL-ZAb-dimethyl 4 keto 7 ethylenedioxy- 1,2,3,4,4a,4b;5,6,7,8;10,10a dodecahydrophenanthrene with an alkali metal borohydride or alkaline earth metal yborohydride to form ,the corresponding l-carboxymethylene-Z-methallyl -2;4b 7 dimethyl 4 hydroxy-7-ethylreacted with an alkali metal in a lower alkanol or in liquid ammonia to produce 1-carboxymethyl -2- methallyl 2,4b dimethyl 4 hydroxy 7 ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene (Compound 4). This compound is reacted with an esterifying agent, preferably an alkyl iodide in the presence of a base and/or a diazoalkane to produce the corresponding 1 carboalkoxymethyl-2-methallyl-2,4b-dimethyl 4 hydroxy-7-ethylenedioxyl-1,2,3,4,4a,4b,5,6,7, 8,10,lOa-dodecahydrophenanthrene (Compound 6). This compound is reacted with an oxidizing agent, preferably under alkaline conditions, thereby forming the corresponding l-carboalkoxymethyl 2-methallyl-2,4b-dimeth yl 4 keto-7-ethylenedioxy-1,2,3,4,4a,4b,5,6,7,8,10,106.-

dodecahydrophenanthrene (Compound 7); alternatively, l-carboxymethyl 2 methallyl-Z,4b-dimethyl-4-hydroxy- 7-ethylenediory l,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrqphenanthrene can be reacted with an oxidizing agent to produce 1-carboxymethyl-2-methallyl-2,4b-dimethyl-4- 6o "keto-7-ethylenedioxy l,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene (Compound 8), which is then reacted with an ester'ifying agent to form the corresponding l-carbba'lkoigymethyl 2 methallyl-2,4b-dimethyl-4- keto-7-ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,10a-dodeca- The latter compound is reacted with osmium tetroxide to form the losmate ester 0f l-carboalkoxymethyl-2-(beta,gamma-dihydroxyisobutyl)12,4b-dimethyl-4-keto 7 et-hylenedioxy 1,2,3,4,4a,4b,5,6,7;8-,l0,10a dodecahydrophenanthrene(Compound 9), which is reacted with an aqueous u alcoholic solution of an alkali metal sulfite or bisulfite to produce the corresponding 1-carboalkoxymethyl-2-(beta,

=CEC-QR Compound 1 compound is reacted, under substantially anhydrous conditions, with a strong alkali thereby forming A -3-ethylenedioxy-I1,16,20-triketo-pregnene (Compound 12). The A -3-ethylenedioxy-l1,16,20-triketo-pregnene is reacted with an organic sulfonylhalide; thereby forming the corresponding sulfonate ester of A -3 -ethylenedio1ty-11,20- diketo-l6-hydroxy-pregnadiene (Compound 13'); which is reacted with hydrogen in the presence of a hydrogenation catalyst to produce A -3-ethy1enedioxy-1l,20-diketo-pregnene (Compound 14). The A -3-ethy1enedioxy-11,20-diketo-pregnene is then reacted with an aqueous mineral acid solution whereupon the ethylenedioxy substituent attached to the 3-carbon atom is hydrolyzed and; at the sametime, the double bond shifts from ring B to ring A to form A -3,11,20 triketopregnene (Compound 15).

The reactions indicated herein above may be chemically represented as follows:

CHI. 7 7

on, =on,

/ i' i o =OH.CQOR =CHCOOH [3s Compound 3 Compound 2 t ta,

- no I no -CH1CO0H CH;COOR' v 0 a o 0 Oompound5 Compound4 Compound6 on CH1 CE; =GH, l

' v H, 0 O

-CH;GOOH CH;COOR' l o o Compound 8 Compound 7 I l i H l /l| OHIOH 1 p on.- o om-h-on =0 H, i H, H, v o o o l -on,'coon'- -om0 oon' -0H5ooopu O l v I 1 v Y Compound9 I 3 Compound 10 v I Compound 11 assigns Compound 12 o josoln" Compound 13 Compound 14 wherein R and R are alkyl radicals and 'R" is an organic radical.

:Although in the foregoing series of-reactions, the substituent in ring A of the polyhydrophenanthrene nucleus istshown as an ethylenedioxygrouping, instead ;of ethylenedioxy, any ke'tal substituent including simple ketals, thioketals, hemi-thioketals, cyclic ketals, cyclic thioketals, and cyclic hemi-tllioketals can be used as the protecting grouping. In place of a ketal substituent, an enol-ether mayIbe used as the protecting group, ifdesired. Accordingly, instead of -l-alkoxyethinyl-y1-hydroxy-2methallyl- 2,4bedimethyll keto-7=ethylenedioxy l,2,3,4,4a,4b,5,6,7, 8,10,10a dodecahydrophenanthrene, any l-alkoxyethinyl- 12-(allyl or alkallyl)-2,4b-dimethyl-4-keto-1,2,3,4,4a,4b,5,

6,7,8,10, lOa-dodecahydrophenanthrene. compound, having .in "the 7-position a ketal slibstituent (including simple .keta'ls, .thioketals, hemi-thioketals, cyclic ketals, cyclic thioketals, and cyclic hemi-thioketals) hydrolyzable to a 7-keto grouping, may be used as starting material in the presently invented process. In 'each of the process operations utilized by us in preparing A -3,ll,2O-triketo-pregnene, the keto group in ring A is blocked by a ketal protecting group (as above defined). At any stage in the process, this keto group may be regenerated by acid hydrolysis whereby the -ketal group is hydrolyzed and,

'at the same time, the double bond shifts from ring B to ring A thus forming an a,[3-unsaturated ketone. It is ordinarily preferred to utilize an ethylenedioxy substituent as the protecting group, and our preferred starting material is 1-alkoxyethinyl-1-hydroxy-2-methallyl-2,4b-di- 'hydroxy' substituent to form 'l-ethoxy-3-keto pentane; the latter compound is treated with ethyl ortho formate and ethanol in the presence of hydrogen chloride to produce 1,3,34riethoxy-pentane which, upon reaction with hot potassium bisulfate, is converted to 3-ethoxyl,3,-pentadiene. The 3-ethoXy-'1,3-pentadiene is reacted with benze- -.qu.inone in accordance withthe Diels-Alder condensation -procedure to. produce -methyl-6-ethoxy-1,4,4a,5,8,8a-hex-1 Compound 15 ahydronaphthalene-1,4-dione which is-then reacted with hydrogen in the :presence of Raney nickel catalyst to form 5-methyl-6-ethoxy-1,2,3,4,4a,5,8,8a-octahydronaphthalene-1,4-dione; the latter compound is reacted :with lithium aluminum hydride toforrn thecorresponding diol, -5=methyl-6-ethoxy-1,2,3,4,4a,5,8;8a octahydronaphthalene-1,4-,diol which is reacted with;a rhydrolyzingyagent to produce 5-methyl6-ketoperhydronaphthalenel,4-dio1. The reactions indicated above are described in 'detailin a -co-pending application .ofone of the I present applicants, Serial No. 216,109, filedMarch l6 ;l,-,now abandoned. The 5 -rnethyl-6-keto-perhydronaphthalene-1,4-diol; isthen reacted with -N-(3-keto-butyl) N,N-diethyl N-methylammoniumiodide in thepresenceof potassium: hydroxide to produce 7- ket0-4b-methyl-1,2,3,4,4a,4b,5,6,7,9,l01.0adodecahydrophenanthrene-1,4-diol; this reaction sdescribed in detail in ycopending application, Serial .No. 228,126,'filed May 24, 1951, new -Patent No. 2,617,828. The 7-keto-4b-rnethyl-l,2,3,4,4a,4b,5,6,7,9,l0,loa dodecahydrophenantherene 1,4 diol is treacted-with ethylene glycol in ethylene dichloridesolution and in thepresence 'of p-toluene sulfonic acid catalyst.thereby forming.1 ,4 dihydroxy-4b-methyl-7-ethylenedioxy 1,2,3, 4-,4a,4b,;6,'l; 8, 10,10a-dodecahydrophenanthrene. The 1,-4.- di hydroxy- .4b-methyl-7Pethylenedioxy l,2,3,4,4a,4b,5,6,7,8,l,0,110avdo decahydrophenanthrene is. reacted with cyclohexanone and aluminum isopropoxidein benzene solution to produce the corresponding 1-keto-4-hydroxya4b rnethyl-7- ethylenedioxy 1,2,3,4,4a,4b,5,6,7',8,10,IOa-dodecahydrophenanthrene. The reactions indicated hereinabovenre described in detailin a co-pending application .of the present applicants, Serial No. 286,808, filed May., 8 195.;2, now abandoned. I '1.

The 1-keto-v4-hydroxy-4b-methyl-7-ethylenedioiiyal,2;3, 4,4a,4b,5,6,7,8,10,l0a-dodecahydrophenanthrene is reacted with methyl iodide in the presenceofpotassium tertiary butoxide in benzene v.therebyforming .1-keto-,2,4bdimethyl-4-hydroxy-7-ethylenedioxy l,2,3,4,4a;4b,5,6,7, 8, -10,10a-dodecahydrophenanthrene; the .latter .compbund is reacted with chromium .trioiriderpyridine,complex ;to form l,4-diketo-2,4b:dimethyl-7-ethylenedioxyfl,2,3;4,4a, 4b,5,6,7,8,10,l0a dodecahydrophenanthrene. ,The methylation reaction indicated hereinabove is described in detail in a co-pending .applicationinwhich one ot-the present applicants is co-inventor, Serial No. 306,488, vfiled August 26, 1952, now abandoned. Theoxidation .reaction indicated hereinabove .is ,describeddn detail ,in

a co-pending application in which one of the present applicants is the sole inventor, Serial No. 292,985, filed June 11, 1952, now abandoned. The 1,4-diketo-2,4bdimethyl-7-ethylenedioxy 1,2,3 ,4,4a,5,6,7, 8,10,10a-dodecahydrophenanthrene is reacted with methallyl iodide in a tertiary butyl alcohol solution of aluminum tertiary butylate, thereby forming 1,4-diketo-2 methyllyl-2,4b-dimethyl 7 ethylenedioxy l,2,3,4,4a,4b,5,6,7,8,l0,10adodecahydrophenanthrene. The latter compound is reacted in ether-benzene solution with an alkoxy acetylene magnesium bromide to produce the corresponding 1'- alkoxy ethinyl-1-hydroXy-2-methallyl-2,4b-dimethyl-4- keto-7-ethylenedioxy-l,2,3,4,4a,4b,5,6,7,8,l0,10adodecahydrophenanthrene.

Alternatively, the l-keto-2,4b-dimethyl-4-hydroxy-7- ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,10a-dodecahydrophenanthrene is reacted with methallyl iodide in a tertiary butyl alcohol solution of aluminum tertiary butylate to produce 1-keto-2-methallyl-2,4b-dimethyl-4-hydroxy-7- ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,10a-dodecahydro phenanthrene which, upon reaction with an alkoxy acetylene magnesium bromide in ether-benzene solution, is converted to the corresponding 1-alkoxyethinyl-l,4-dihydroxy 2-methallyl-2,4b-dimethyl-7-ethylenedioxy-1,2, 3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene. The reactions indicated hereinabove are described in detail in two copending applications of the present applicants, Serial No. 306,509, filed August 26, 1952, now abandoned, and Serial No. 308,172, filed September 5, 1952, now abandoned. Where it is desired to utilize another cyclic ketal or other ketal substituent (as defined above) or an enol-ether substituent to protect the 7-keto grouping, this is introduced in the foregoing procedure by reacting the intermediate 1,4-dihydroxy-7-keto-4b-methyl-1, 2,3,4,4a,4b,5,6,7,9,10,10a dodecahydrophenanthrene under substantially anhydrous conditions and in the presence of an acid catalyst, with a lower alkanol such as an excess amount of methanol, ethanol, propanol, bu-

- tanol, and the like, or an excess of another low molecular weight glycol such as propylene glycol, butylene glycol,

or an excess of a thioglycol or dithioglycol such as ethanedithiol, propane 1,2-dithiol, s mercapto-ethanol,

fl-mercapto-propanol, and the like. It it is desired to use an enol-ether as the protecting group, the 1,4-dihydroxy 7-keto 4b-methyl-1,2,3,4,4a,4b,5,6,7,9,10,10adodecahydrophenanthrene is reacted under substantially anhydrous conditions in the presence of an acid catalyst with an alkyl ortho formate.

The rearrangement of the l-alkoxyethinyl-1-hydroxy2- methallyl 2,4b dimethyl-4-keto-7-ethylenedioxy-l,2,3,4,

4a,4b,5,6,7,8,l0,lOa-dodecahydrophenanthrene, its 2-allyl and 2-alkallyl homolog, and other 7-ketals thereof, is carried out by bringing this compound into intimate contact with an aqueous mineral acid in solution in an organic solvent for the compound, for example a cyclic ether such as tetrahydrofuran, tetrahydropyran, dioxane or an alkanol such as ethanol, isopropanol, butanol and the like, under which conditions the ketal or enol ether substituent attached to the C-7-carbon atom is not appreciably hydrolyzed. We ordinarily utilize tetrahydrofuran as the organic solvent in conjunction with 10% aqueous sulfuric acid solution, and allow the slightly exothermic reaction which takes place to proceed at a temperature of about 25-30 C. Under these conditions, the reaction is ordinarily complete in about three and one-half hours. In accordance with this procedure, there is obtained the desired 1-carboalkoxymethylene-2-methallyl-2, 4b-dimethyl 4 keto-7-ethylenedioxy-1,2,3,4,4a,4b,5,6,7, 8,l0,lOa-dodecahydrophenanthrene admixed with a byproduct, 1 carboalkaxymethyl-l-hydroxy-2-methyl-2,4b-

dimethyl 4 keto-7-ethylenedioxy-l,2,3,4,4a,4b,5,6,7,8,

10,10a-dodecahydrophenanthrene. These two products can be conveniently isolated from the reaction mixture by neutralizing the mineral acid with a mildly aqueous alkaline solution, preferably a saturated aqueous solution of sodium bicarbonate, distilling the organic solvent under reduced pressure, and extracting the oil which separates during distillation into the ether. After washing, drying and evaporating the ether extract, there is obtained a residual oily material from which it is possible to fractionally crystallize the foregoing components in substantially pure form. It is ordinarily preferred, however, to separate these two products in pure form by chromatography on acid-washed alumina. This is accomplished by dissolving the residual oily material in benzene-petroleum ether, contacting this solution with acid-washed alumina and eluting the adsorbate with a mixture of petroleum ether-ether. From the eluates richer in the petroleum ether component is obtained the l-carboalkoxymethylene- Z-methallyl 2,4b dimethyl-4-keto-7-ethylenedioxy-l,2, 3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene and from the following fractions which contain a relatively higher proportion of ether is obtained the l-carboalkoxymethyl 1 hydroxy-2-methallyl-2,4b-dimethyl-4-keto-7- ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,10a-dodecahydrophenanthrene.

The saponification of the ester grouping in the l-carboalkoxymethylene 2 methallyl-2,4b-dimethyl-4-keto-7- ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,10a-dodecahydrophenanthrene is conducted utilizing an alkaline hydrolyzing agent since the 7-position substituent is unstable under the conditions normally encountered in the acid hydrolysis of esters. The hydrolysis is conveniently carried out utilizing an aqueous methanolic solution containing potassium carbonate and a small amount of potassium hydroxide, but other alkaline hydrolyzing agents can be utilized if desired. When this preferred hydrolyzing agent is utilized, saponification may be carried out at room temperature, or more rapidly, if desired, by heating the reactants at the reflux temperature of the solution. The methanol is evaporated under reduced pressure, and the aqueous mixture diluted with approximately an equal volume of water, whereupon the potassium salt of 2-carboxymethylene 2 methallyl 2,4b dimethyl-4-keto-7- ethylenedioxy 1,2,3,4,4a,4b,5,6,'7,8,10,l0a-dodecahydrophenanthrene may precipitate as an oil. The aqueous solution or suspension is then extracted with ether, and the aqueous mixture is acidified with a mildly acidic reagent such as sodium dihydrogen phosphate. The acidic material which separates is extracted with chloroform, the chloroform extracts are dried and evaporated under reduced pressure to give 1-carboxymethylene-2-methallyl- 2,4b-dimethyl 4 keto-7-ethylenedioxy-l,2,3,4,4a,4b,5, 6,7,8,10,l0a dodecahydrophenanthrene. This material may be further purified by washing with ether and recrystallizing the material from ethyl acetate.

As set forth herein above, the l-carboxymethylene-Z- methallyl 2,4b -'dimethyl 4 keto 7 ethylenedioxy- 1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene can be converted directly to l-carboxymethyl-2-methallyl- 2,4b dimethyl 4 hydroxy 7 ethylenedioxy 1,2,3, 4,4a,4b,5,6,7,8,l0,10a dodecahydrophenanthrene by reaction With an alkali metal, such as sodium, lithium, or potassium, or this reaction can be carried out' in two operations, first reducing the 4-keto substituent to hydroxy utilizing an alkali metal borohydride such as sodium borohydride, lithium borohydride, potassium borohydride or an alkaline earth metal borohydride such as calcium borohydride, and then reducing the l-carboxymethylene substituent utilizing the alkali metal.

The reaction between the l-carboxymethylene-Z- methallyl 2,4b dimethyl 4 keto 7 ethylenedioxy 1,2, 3,4,4a,4b,5, 6,7,8,l0,10a dodecahydrophenanthrene and the alkali metal borohydride or alkaline earth metal borohydride is conducted by suspending the hydrophenanthrene compound in water or in aqueous organic solvent such as aqueous tetrahydrofuran, aqueous dioxane, aqueous alkanol, and the like, and adding the alkali metal or alkaline earth metal borohydride cautiously to the mixture. After all the reducing agent has dissolved, the reessence hydrogen phosphate for this acidification. The product which 'precipitates is extratiteiwith :an organic solvent such as chloroform. The chloroform extracts are washed, dried and'evaporated in vacuo to give an oil which can 'be cry stallized from ether to give crystalline 1 carboxymethyl'ene 2 -methallyl 2,4b din1ethyl 4- hydro'xy 7 -ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8, 10,1021- dodecahydrophenanthrene. 1

The latter product or, if desired, the starting-'hcarb'oxymethylene 2 methallyl 2,4b dimethyl 4 keto -'7- ethylenedioxy 1 ,2,3,4,'4a,4b,'5,6,-7 ,-8, 10, 10a --dodecahydrophe'nanthrene is reacted with an alkali m'etal su'ch as metallic lithiumfsodiu'm or 'potassiurrnand the like, in solution in a lower alkanoland/or in liquid ammonia.

Where metallic lithium or potassium "are used as the reducing agents, it is prefe'rred to useliquid ammonia. The reaction system which has been 'found'most advantageous is potassium liquid -ammonia-isopropanol. The

"reaction between the 1-carboxymethylene-2-methallyl 2,

4b dimethyl 4 (keto or hydroxy) 7 ethylenedioxy- '1,2,3,4,4a,5,6,7,8,10,10a dodecahydrophenanthrene and metallic lithium or potassium is conveniently carried 0 out -'by suspendingthe hydrophenanthrene compound in liquid ammonia and addingthe alkali metal portion-wise to the suspension. Itdesired,naloweralkanol s-uch as "ethanol, Ibutanol, and-the likernay be added tothe re- "action mixtureyalthough the reduction reaction will occur in the absence of the alkanol, the yield of the desired product 'is improved, in some cases, by the'use of the alkanol. The liquid ammonia 'reactionmixture -is"stirred at the'boiling point of-liquid ammonia until' the'ammonia has evaporated. The crude reaction mixture'is treated withbenzene, and, if necessary, a small-amount of ethyl acetate-or alcohol is added to destroy 'the 'e-xce'ss alkali metal. The resulting mixture is then diluted with water, the benzene layer is discarded, and the alkaline layer containing thereduction pro'ductis solidified. The material which precipitates is extracted with chloroform, "and the chloroform extractis washed, dried and evaporated. The oily materialthus obtained iserystallized'by heating with ether to give crude l 'carboxym'ethyl 2- methallyl 2,4b dimethyl -'4 hydroxy 7 ethylenedioxy l,2,3,4,4a,-5,6,7,8;l0,10a --dodecahydrophenan- 'threne.

When sodium or potassium'is used-as the reducing agent,-the reaction is conveniently carried out by bringing together the 1 carboxymethylene 2 -"methal1yl --2 ,4bdimethyl 4 (keto or'hydroxy) --'7- ethylenedioxy l, 2,3,4;4a,4b,5,6,7,8,l0,l0a dodecahydrophenanthrene;alkali metal,-and ahot lower alkanol and stirring theresulting mixture under reflux for aperiod-of about fifteen minutes.

one-half volume in vacuo diluted with water and the 'aqueoussolution is carefully acidified. The acidic aqueous mixture is extracted with chloroform, and the chloro form extract is dried andevaporated invacuo. The residual material consists of crude l-carboxym'ethyl-Z-methallyl 2,4b dimethyl 4 hydroxy -7 ethylenedioxy- 1,2,3,4,4a,5,6,7,8,l0,10a dodccahydrophenanthrene.

When the reduction is carried out utilizing -as -starting material the 1-- carboxymethylene 2 methallyl 7 2,4bdimethyl 4 keto 7 ethylenedioxy 1,2,3,4,4a,5,6, 7,8,10,10a dodecahydrophenanthrene, there may be obtained, in addition to the -1-carboxymethyl-2-methallylf2,

4b dimethyl 4 hydroxy 7 ethylenedioxy -"l,2 ,3,:4, 4a,4b,5,6,7,8,10,1Oa -dodecahydrophenanthrene, 1 a f small 45 complete in about 15 hours.

The reaction mixture is evaporated to about '5 6,7,8, 10,IOa-dodecahydrophenanthrene can be carried out by any of the usual methods of esterification but, in view of .the ease of hydrolysis of the metal substituent in the c7=p'osit-ion, it is ordinarilypreferred to conduct this esterification under alkaline conditions usinga diazoalkane or II) -analkyl iodide in thetpresence of a base as the esterifying agent. The reaction utilizing a diazoalkane such as diazomethane or diazoethane is conveniently carried out ':by dissolving the 1-carboxymethyl-2-methallyl-2,4b-dimethyl 4 '(hdyroxy orke'to) 7 ethylenedioxy l,

-1 5 2,3;4;4a,4b,-5,6,7,8,l0,10a dodecahydrophenanthrenein an organic solvent suchas ether and adding to this *solutionan excess of the diazoalkane in an inert organic solvent m'edium such as ether. The resulting solution is allowed'to stand at approximately room temperature until 0 the evolution 'of nitrogen ceases, the solvents are evaporated, and the residual oil is crystallized to give l-carboalkoxyinethyl '2 methallyl 2,4b dimethyl 4 (hy- -drox-y or ketoy- 7 -ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,

lO,1'oa tlodecahy'drophenanthrene.

" The 1-carboalkoxymethyl-Z-methallyl-2,4b-dimethyl-4- hydroxy- 7 ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,10a- =dodecahydrophenanthrene can be converted by reaction with an oxidizing agent to the corresponding 4-ket'o derivative, which is alternatively obtained by the esterification of the 1-carboalkoxymethyl-2-methallyl-2,4b-dime'thyll-keto 7 --ethylenedioxy-l,2,3,4,4a,5,6;7,8,10,10a-

dodecahydrophen'anthrene as described hereinabove. As ciXidiZing'agent 'for this reaction,we ordinarily prefer to utilize chromium trioxide-pyridine complex, although 5 other 'oxid i'zing agents such as chromic acid may be em- 'ployed if desired. Using the preferred oxidant, the

'l cai'boalkoxymethyl -2 methallyl 2,4b -dimethyl-4-hy droxy-7 --ethylenedioxy l,2,3,4,4a,4b,5,6,7,8,10,10ado- -decahydrophenanthrene is dissolved in pyridine and mixed 0 with-thecomplex formed by adding chromium trioxide to anexcess of pyridine. The resulting mixture is allowed -to stand ata temperature within the range of about 0 C.

to l-00C. for a period of time, depending upon the temperature; "at room temperature, the reaction is ordinarily The reaction mixture isdiluted "with water and the aqueous solution is extracted 'Wifh'fl Water-immiscible organic solvent such as ether. The organic solvent extracts are washed with-Water,-dried, and "the solvent evaporated. The residual oil is crystal- '50 lized to give 1-carboalkoxymethyl-2-methallyl-2,4b=dimethyl-4-keto-7 ethylenedioxy l,2,3,4,4a,4b,5,6,7,8,l0, '10a do'decahydrophenanthrene.

-Further oxidation of -the latter compound converts the methylene-substituent in the methallyl radical to a keto '55 grouping. "This can'be accomplished-in a two-step oxidation utilizing'osmium tetroxide followed by periodic acid *or in'a single-step utilizing ozone. Where the osmium tetroxideprocedure is used, the l-carboalkoxymethyl-Z- *met'hallyl-2,4b-dimethyl-4-keto-7-ethylenedioxy-l,2,3,4,4a,

' 0 4b,5,6,7,8,10,10a dodecahydrophenanthrene is dissolved in a 'drybt'her'benzene solution and approximately one equivalent'ofosmium tetroxide is added to the solution. In a'fe'w minutes the osmate ester of the l-carboalkoxymethyl- 2 (beta,gan1ma dihydroxy isobutyl) 2,4b-dimet yl- 7 ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,10a-dodecahydrophenanthrene precipitates, and the resulting mixture -is-alloWed-to stand at'about room temperature for aperidd'of about one hour. At the end of this period, the reaction is substantially complete. An or- 70 gani'c'solvent for the'osmate ester, for example a lower amount of 1 carboxyr'nethyl -"2 methallyl 2, 4b"- 'di- '15 as 'amaqueoussolution of an alkali metal sulfite or bition is evaporated under reduced pressure.

,in a few minutes.

alkanol, such as ethanol, and a cyclic ether, such as tetrahydrofuran and the like, and to this solution are added pyridine and an aqueous solution of periodic acid. .The glycol cleavage which takes place is ordinarily complete The reaction mixture is diluted with water, and the aqueous reaction mixture is extracted with an organic solvent such as ether. tract is washed, dried, and evaporated to give an oily prod- .uct which can be crystallized to give substantially pure l-carboalkoxymethyl 2-acetonyl-2,4b-dimethyl-4-keto-7- ethylenedioxy-1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene.

When the conversion of the 2-methallylsubstituent to an acetonyl radical is conducted utilizing ozone instead of osmium tetroxide followed by periodic acid, the 1-carbo alkoxymethyl-Z-methallyl-2,4b dimethyl 4-keto-7-ethylenedioxy-l,2,3,4,4a,4b,5,6,7,8,10,10a-dodecahydrophenanthrene is dissolved in a lower alkanol such as methanol, the solution is cooled to a low temperature of about 80. C., and ozonized oxygen containing one equivalent of ozone based on the hydrophenanthrene compound is passed through the solution. The resulting mixture is warmed to approximately 0 C., and the ozonide product in the reaction mixture is decomposed under reductive conditions either by means of a small amount of zinc and aqueous acetic acid, or catalytically by contacting the ozonide in an aqueous medium with hydrogen and .a platinum catalyst. When the ozonide is reacted with zinc and aqueous acetic acid, the reaction mixture is made slightly alkaline, filtered and the solvents evaporated therefrom in vacuo at a temperature below about 20 C. The residual material is extracted with ether, the ethereal solution is chromatographed on acid-washed alumina and the alumina-adsorbate is eluted utilizing ether-petroleum ether. Upon evaporation of the ether-petroleum ether eluate, there is obtained 1-carboalkoxymethyl-Z-acetonyl- 2,4b-dimethyl-4-keto-7-ethylenedioxy 1,2,3,4,4a,4b,5,6,7, 8, 10, a-dodecahydrophenanthrene. v

We then prepare a substantially anhydrous solutionof 1-carboalkoxymethyl-2-acetonyl-2,4b dimethyl-4-keto-7- ethylenedioxy-1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene in an aromatic hydrocarbon such as ben zene, toluene, and the like. This solution is brought into contact with a solid anhydrous, strongly basic material, for example in alkali metal alkoxide, such as sodium methoxide, potassium t-butoxide, an alkali metal, such as metallic sodium, an alkali metal hydride, such as sodium hydride, an alkali metal amide such as sodamide, and the like. The resulting mixture is ordinarily stirred at a temperature within the range of about to 50 C. although temperatures somewhat below or above this rangemay be used, if desired. When the reaction is carried, out at The organic solvent exabout room temperature, the cyclization is substantially complete in approximately ten hours. The reaction mixture is poured into water and immediately acidified with an excess of a mildly acidic reagent such as an aqueous solution of primary sodium phosphate. The acidified solution is extracted with an organic solvent such as chloroform and the solvent extract dried, filtered and evaporated to give crystalline A -3-ethylenedioxy-l1,16,

. ZO-triketQ-pregnene, which can be further purified if desired by recrystallization. Acid hydrolysis of the A -3- i2 ethylenedioxy-l1,16,20-t1iketo-pregnene gives A -3,11,16, ZO-tetraketo-pregnene.

The A -3-ethylenedioxy-l1,16,20 triketo pregnene' is then reacted with an organic sulfonyl chloride, preferably p-toluene sulfonyl chloride. This reaction is carried out dissolving the pregnene compound in a tertiary amine such as pyridine and adding the organic sulfonyl chloride to the resulting solution. The reaction is allowed to proceed at about room temperature under which conditions the reaction is ordinarily complete in about twelve to twenty-four hours. The excess organic sulfonyl chloride and pyridine ;are neutralized by the addition of a mildly alkaline aqueous solution such as aqueous sodium bicarbonate,

and the resulting mixture is agitated for a short period of time, during which time the sulfonate crystallizes. An organic solvent such as benzene is added to the reaction mixture, the mixture is poured into ice water, and the organic layer is separated. The organic layer is washed with water, dried and evaporated in vacuo. The residual ,material can be purified by recrystallization to give the 16-sulfonate ester of A -3-ethylenedioxy-16-hydroxy- 11,ZO-diketo-pregnadiene in substantially pure form.

The catalytic hydrogenation of the latter material is conveniently carried out by dissolving the 16-su1fonate ester of A -3-ethylenedioxy-16-hydroxy-l1,20-diketopregnadiene in benzene, adding a hydrogenation catalyst, such as palladium on barium carbonate, and contacting the mixture with hydrogen at atmospheric pressure, or preferably at superatmospheric pressure. When the hydrogenation reaction is carried out at room temperature and at a pressure of about forty pounds per square inch, the reaction is substantially complete in about twenty hours. It is ordinarily preferred to add additional amounts of catalyst during the course of the hydrogenation. The hydrogenation mixture is filtered, and the filtered solution is evaporated in vacuo. The residual oil is crystallized to give substantially pure A -3-ethylenedioxy-l1,20-diketo-pregnene.

The latter compound is treated with a hydrolyzing agent, preferably an aqueous mineral acid such ashydrochloric acid, perchloric acid, p-toluene sulfonic acid, and the like, thereby hydrolyzing the ketal substitutent in the 3-position of the molecule. When aqueous perchloric acid is employed, the hydrolysis is conveniently carried out by dissolving the A -3-ethylenedioxy-11,20-diketopregnene in an organic solvent such as tetrahydrofuran, adding a dilute aqueous solution of perchloric acid to the resulting solution, and allowing the resulting mixture to stand at about room temperature for a period of about three to four hours. The solvents are evaporated in vacuo, and the residual material is extracted with an organic solvent such as chloroform. The chloroform extract is dried, the chloroform evaporated in vacuo, and the residual material is crystallized to give substantially pure A -3, 1 1,20-triketo-pregnene.

The stereoisomeric form of A -3,l1,20-triketo-pregnene .having a melting point of about l-l76 C. possesses the stereoisomeric configuration characteristic of the naturally-occurring steroid hormones such as progesterone.

We refer to this stereoisomer by the name of ll-keto progesterone. This compound is obtained in the form of a racemic mixture of the dand lforms, and is referred to more specifically as dl-ll-keto-progesterone.

The 3-ethylenedioxy derivative of dl-A -3,l1,20-triketopregnene of melting point l75176 C. obtained as hereinabove described may be converted to the therapeutically active material 3,1l,ZO-triketo-l7a-hydroxy-2l-acetoxy- A -pregnene as follows: dl-3-ethylenedioxy-11,20-diketo- A -pregnene is treated with dimethyl oxalate and then with alkali to form the C21 oxalyl acid derivative. On formation of the strychnine salts of the components of this race- Imic mixture the d-salt precipitates and may be recovered by'filtration. Decomposition of this strychnine salt 'and tog'raphed on acid-washed alumina.

ensues 7 13 lifiedioXy-I1,20-diketo-A -pregnene identicalwith that obtained from naturally occurring materials.

Iodination under alkaline conditions of the natural isomer of the 21-oxalyl acid of 3-ethylenedioxy-11,20-

'diketo-A pre'gene, which may be obtained in the above permangante to I i-ethylenedioxy 11,- diketo-l7a-hydrctxy-Z1-acetoxy-A -pregnene. 3,11,20 triketo 17 a-hydroxy-2l-acetoxy-A -pregnene, alternatively known as tortisene acetate, may be prepared by acid hydrolysis of the above mentioned 3-ethylene dioxy-11,20-diketo-17ahydroxy-21-acetoxy-A -pregnene.

The 3 ethylenedioxy derivative of d1-3,11,20-triketo- A '-pregnene may also be converted into dl-3,11,20-triketol7ot-hydroxy-21-acetoxy-A -pregnene by the procedure hereinabove described.

In addition to being useful as an intermediate in the total synthesis of cortisone acetate, dl-ll-keto-proges- =terone has been shown to possess greater cortisonelike activity (as measured by the granuloma inhibition test) than either d-ll-keto-progesterone or cortisone. fact that dl-l'l-keto-pro'gesterone possess greater cortisone- The activity than d-ll keto-p'rogesterone is particularly un- -obvious in view of the fact that the corresponding l-isomer is substantially inactive.

The following examples illustrate methods of carrying out'the present invention, but it is to be understood that example is given for purposes of illustration and not of limitation.

Example 1 I To a solution of 24 g. of 1ethoxyethinyl-2-methallyl- 2,4b dimethyl 7 ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,

10,10a dodecahydrophenanthrene 1 o1 4 one (M.P. 133--134 C.) in 160 ml. of tetrahydrofuran was added 101111. of 10% aqueous sulfuric acid. The resulting mix- 1 ture was maintained at a temperature within the range of 27 C. to 29 C. for aperiod of about three and onehalf hours. At the'end of this time, an excess of a satu- -rated aqueous solution of sodium bicarbonate was added to the reaction mixture, and the tetrahydrofuran was evaporated from the aqueous mixture under reduced pressure. The oil which separated was extracted into ether; the "ether extract was washed once with water, dried over "sodium sulfate, and the ether was evaporated. The

residual oily material was dissolved in ether and chroma- The adsorbate was 'eluted with mixtures of ether and petroleum ether; upon evaporation of the 8:2 petroleum ether-ether eluate there was obtained 1-carboethoxymethy1ene-2-methallyl-2,4b-

, di-methyl-7-ethylenedioxy-1,2,3,4,4a,4b,5,6,7,8,10,10a-do- .decahydrophenanthrene-4-one; upon evaporation of the 7:3 petroleum ether-ether eluate there was obtained 1- carboethoxymethyl-2-methallyl-2,4b-dimethyl -7-ethy1enedi'oxy l,2,3,4,4a,4b,5,6,7,8,10,109. dodecahydrophenanthrene-l-ol-4-one having an MP. of 99l0-1 C.

"In accordance with the foregoing experimental procedure and utilizing as starting material the stereoisomer of 1 ethoxyethinyl 2 methallyl 2,4b dimethyl 7- ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanethrene-l-ol-4-one having an M. P. of 133- 134 C., there Was obtained the stereoisomer of l-carboethoxymethyl 2 methallyl 2,4b dimethyl 7 ethzfiylenedioxy l,2,3,4,4a,4b,'5,'6,7,8,10,10a dodecahydroand the chloroform extract was dried over sodium suland the stereoisomer of l' ca'rb'oethoxymethylene-2-methallyl 2,4b dimethyl 7 t ethylenedioxy 1,2,3,4,4a, 4b,5,6,7,8,10,10a-dodecahydrophenanthrenei-one having an MP. of 133134 C. and 151l52 C. (dimorphic).

By using a stereochernical modification of the above 1- ethoxyethinyl 2 methallyl 2,4b dimethyl 7 ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene-1-ol-4-one starting material having an MP.

.of 131-132" C. there was obtained the stereoisomer of 1 carboethoxymethyl 2 methallyl 2,4b dimethyl- 7 ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene-1-ol-4-one having an M.P. of 146 C.

, and the stereoisomer of 1-carboethoxymethylene-2-methallyl 2,4b dimethyl 7 ethylenedioxy 1,2,3,4,4a,4b, 5,6,7,8,10,10a dodecahydrophenanthrene 4 one having an MP; of 94-96 C.

Example 2 A suspension of 4.1 g. "of '1-carboethoxymethylene-2- methallyl 2,4b dimethyl -'7 ethylenedioxy l,2,3,4,

4a, 5,6,7,8,10,10a 'dodecahydroph'enanthrene 4 one 'in 50 of methanol and 50 ml. of water containing 10 g. of potassium carbonate and 1 g. of potassium hysalt of l-carboxymethylene 2-methallyl-2,4b-dimethyl-7- ethylenedioxy '1,2,3,4,4a,4b,5,6,7,8,10,10a-dodecahydrophenanthrene-4-one separated as an oil, and approximately 50 ml. of Water was added to dissolve the salt. 'The'a'queo usmixture was extracted "once with ether, and then'acidified with excess sodium 'dihydrogen phosphate. The acidified mixture was then extracted with chloroform,

:lyl 2,4b dimethyl 7 ethylenedioxy 1,2,3,4,4a;4b,

5,6,7,8,'10,10a-dodecahydrophenanthrene-4-one.

In accordance With'the foregoing experimental procedure and utilizingas starting material the stereoisomer of 1 carboethoxymethylene 2 methallyl 2,4b dimethyl- 7 ethylenedioxy .1,2,3,4,4a,4b,5,6,7,8,10,10a dodeca- 'hydrophenanthrene-4-one having an.M.P. of 133-134 C 15 1.2 C., there was obtained the stereoisomer of 'l-carboxymethylene 2 methallyl 2,4b dimethyl 7- ethylenedioxy .1,2',3,4,4a,4b,5,6,7,8,1.0,10a dodecahydrophenanthrene-4-one having an M.P of 223-225 C.

When the stereoisomer of .l-carboethoxymethylene 2- methallyl 2,4b dimethyl 7 ethylenedioxy 1,2,3,4, 4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene 4*-one having an MP. of 949.6 C. was used as starting material and the saponificationconducted as described inithe first paragraph of the present example exceptthat the potassium hydroxide Was omitted from the saponification mixture, there was obtained the stereoisomer of l-carboxymethylene 2 methallyl 2,4b dimethyl 7 ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene-4-one having anM.P. of 203'205 C.

A solution containing about '50 mg. of l-carboxymethylene 2 methallyl 2,4b dimethyl 7 ethylenedioxy- 1,2,3,4,4b,5,6,7,8,10,10a dodecahydrophenanthrene 4- one and about 15 mg. of p-toluene sulfonic acid in about 3 ml. of acetone was heated under reflux for a period of approximately twenty minutes. The acetone reaction mixture was diluted with water and the resulting aqueous mixture was extracted with chloroform. The chloro- ;.form extract was dried and evaporated to dryness to give 1 carboxymethylene 2 methallyl 2,4b dimethyl- Phenanthrene-l-ol-one having an M. P. of 99-101" C. 4,7-di0ne.

Example 3 5,6,7,8,l0,la-dodecahydrophenanthrene-4-one was suspended in ml. of water. One gram of sodium borohydride was added cautiously until the initial reaction was completed. After all of the reducing agent had dissolved, .the mixture was heated at 100 C. for three hours. The reaction mixture was cooled, acidified with sodium dihydrogen phosphate, and the acidified mixture extracted with chloroform. The chloroform extract was Washed with water, dried over anhydrous sodium sulfate, and filtered, and the chloroform was evaporated from the filtered solution in vacuo at a bath temperature of less than about 40 C. The residual oil was crystallized from ether, and recrystallized from ethyl acetate to give substantially pure 1-carboxymethylene-2-methallyl-2,4b-dimethyl 7 ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,1()a dodecahydrophenanthrene-4-ol.

In accordance with the foregoing procedure and utilizing as starting material the stereoisomer of l-carboxymethylene 2 methallyl 2,4b dimethyl 7 ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene-4-one having an M.P. of 223225 C. there was obtained the stereoisomer of l-carboxymethylene-Z-methallyl 2,4b dimethyl 7 ethylenedioxy 1,2,3,4,4a,4b, 5,6,7,8,l0,10a dodecahydrophenanthrene 4 01 having an M.P. of 2l1214 C.

Upon heating, under reflux, a solution of 50 mg. of l-carboxymethylene-2-methallyl-2,4b-dimethyl 7 ethylenedioxy-1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene-4-ol and mg. of p-toluene sulfonic acid in 3 ml. of acetone for a period of about minutes, there is obtained l-carboxymethylene-2-methallyl-2,4b-dimethyl-1,2,3,4,4a,4b,5,6,7,10,10a dodecahydrophenanthrene- 4-ol-7-one.

Example 4 during which the addition of the lithium was continued;

a total of about 500 mg. of lithium was used. The excess ammonia was evaporated from the reaction mixture at room temperature, about 200 ml. of benzene was added, and ethyl acetate was then added cautiously to destroy the excess lithium. One hundred and fifty milliliters of water was added to the mixture and the benzene layer was discarded. The alkaline aqueous layer was acidified with excess sodium dihydrogen phosphate and the acidified aqueous mixture extracted with chloroform. The chloroform extract was washed with water, dried over anhydrous sodium sulfate, filtered, and the chloroform evaporated from the filtered solution under reduced pressure. The residual oil was covered with 50 ml. of ether and the mixture heated under reflux for about fifteen minutes. The crystalline precipitate which formed was recovered by cooling the ethereal mixture and filtering. This crystalline material was fractionally crystallized from acetonitrile to give 1-carboxymethyl-2-methallyl- 2,4b-dimethyl-7 ethylenedioxy l,2,3,4,4a,4b,5,6,7,8,10, lOa-dodecahydrophenanthrene-4-one, which crystallized first, and l-carboxymethyl-2-methallyl-2,4b-dimethyl-7- ethylenedioxy-1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydro-- phenanthrene-4-ol (the more soluble compound).

In accordance with the foregoing experimental procedure and utilizing as starting material the stereoisomer of. 1-carboxymethylene-Zmethallyl-2,413-dimethyl-7 ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,10a dodeca'hydro- '16 phenanthrene-4-one having an M.P. of 223-225 C., there were obtained the stereoisomer of l-carboxymethyl-Z- methallyl-2,4b-dimethyl-7-ethylenedioxy 1,2,3,4,4a,4b,5, 6,7,8,10,10a-dodecahydrophenanthrene-4-one having an M.P. of 201-203 C., and two stereoisomers of ,I-carboxymethyl-Z-methallyl-2,4bdimethyl-7 ethylenedioxy- 1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene-4- 01, one of which has an M.P. of 226-228 C. and the other an M.P. of 234235 C.

When the stereoisomer of 1-carboxymethyI-Z-methallyl- 2,4b-dimethyl-7-ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10, 10a-dodecahydrophenanthrene-4-one having an M.P. of 203205 C. was used as starting material there were obtained two stereoisomers of 1-carboxymethyl-Z-methallyl- 2,4b-dimethyl-7 ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,l0, 10a-dodecahydrophenanthrene-4-ol one of which has an M.P. of 255-257 C. and the other an M.P.of216- When 1-carboxymethylene-2-methallyl-2,4b dimethyl- 7-.ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,10a --dodecahydrophenanthrene-4-ol was utilized as starting material in the foregoing procedure, the product obtained was l-carboxymethyl-2-methallyl-2,4b-dimethyl-7 ethylenedioxy- 1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthreneyl-2-methallyl-2,4b-dimethyl- 1,2,3,4,4a,4b,5,6,7,9,10,108.-

dodecahydrophenanthrene-4-ol-7-one. When the stereoisomer of. 1-carboxymethyl-Z-methallyl-2,4b-dimethyl-7- ethylenedioxy-1,2,3,4,4a,4b,5,6,7,8,10,l0a dodecahydrophenanthrene-4-ol having an M.P. of 255-257 C. was hydrolyzed in accordance with the foregoing procedure there was obtained the stereoisomer of l-carboxymethyl- 2-methallyl-2,4b dimethyl 1,2,3,4,4a,4b,5,6,7,9,10,10adodecahydrophenanthrene-4-ol-7-one having an M.P."of 215-217 C; when the stereoisomer of l-carboxymethyl- Z-methallyl-2,4b,-dimethyl-7 ethylenedioxy 1,2,3,4,4a, 4b,5,6,7,8,10,10a-dodecahydrophenanthrene-4 01 having M.P. of 216-220 C. was similarly hydrolyzed'there was obtained the stereoisomer of l-carboxymethyl-Z-methallyl-2,4b-dimethyl 1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene-4-ol-7-one having an M.P. of 192 C.

When 1-carboxymethyl-Z-metha1lyl-2,4b dimethyl 7- ethylenedioxy-l,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene-4-one is similarly hydrolyzed using an acetone solution of p-toluene sulfonic acid, there is obtained 1-carboxymethyl-2-methallyl-2Ala-dimethyl-1,2,3,4, 4a,4b,5,6,7,9,10,10a-dodecahydrophenanthrene-4,7 -dione.

Example 5 One and two-tenths gram of sodium metal was added to 20 ml. of refluxing ethyl alcohol, followed immediately by one-half gram of l-carboxymethylene-2-methallyb2, 4b-dimethyl-7-ethylenedioxy- 1,2,3,4,4a,4b,5,6,7,8,10,10adodecahydrophenanthrene-4-one. The resulting mixture was stirred vigorously for a period of about fifteen minutes. The reaction mixture was evaporated to one-half volume in vacuo, and the concentrated solution was diluted with water. The aqueous solution was extracted with chloroform, and this extract, after being dried, was evaporated to dryness in Vacuo. The residual crystalline material was fractionally crystallized from scetonitrile to give substantially pure 1-carboxymethyl-Z-methally1-2,4bdimethyl-7-ethylenedioxy- 1,2,3,4,4a,4b,5,6,7,8,-10,10a-d0 decahydrophenanthrene-4-ol.

In accordance with the foregoing experimental procedure and utilizing as Starting material the stereoisomer of 1-carboxymethylene-2-methallyl-2,4b-dimethyl-7 ethyllenedioxy-1,2,3,4,4a,4b,5,6,7,8,10,10a-dodecahydrophenanthrene-4-one having an M.P. of 203205 C., there was obtained the stereoisomer of l-carboxymethyl-3-methallyl-2,4b-dimethyl 7 ethylenedioxy-1,2,3,4,4a,4b,5,6,7,8, l0,10a-dodecahydrophenanthrene-4-ol having an M.P. of 255-257 C. 1

Example 6 One part of 1 carboxymethylene 2 methallyl-2,4bdimethyl 7 ethylenedioxy-1,2,3,4,4a,4b,5,6,7,8,10,10adodecahydrophenanthrene-4-one (M.P. 203-205 C.) was reacted with about 2.4 parts of sodium metal utilizing the same procedure as that described in Example 5 hereinabove except that n-butanol was used for the reduction medium in place of ethyl alcohol. The reaction mixture was worked up as in Example 5 to give substantially pure l-carboxymethyl-2-methallyl-2,4b-dimethyl 7 ethylene- I dioxy l,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene-4-ol (M.P. 255-257 C.).

Example 7 A solution of 2.75 g. of l-carboxymethyl-2-methallyl- 2,4b-dimethyl-7 ethylenedioxy l,2,3,4,4a,4b,5,6,7,8,10, a-dodecahydrophenanthrenel-ol was treated with an excess of diazomethane in ether. After standing overnight at room temperature, the solvents were removed by evaporation. The residual oil was crystallized from ether, and the crystalline material thus obtained recrystallized from a mixture of ethyl acetate, ether, and petroleum ether to give substantially pure l-carbomethoxymethyl-Z- methallyl 2,4b-dimethyl 7-ethylenedioxy-l,2,3,4,4a,4b, 5,6,7,8,10,10a-dodecahydrophenanthrene-4-01.

In accordance with the foregoing experimental procedure and utilizing as starting material the stereoisomer of 1-carboxymethyl 2 methallyl 2,4b dimethyl 7- ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,103. dodecahydrophenanthrene-4-ol having an M.P. of 226-228" C., there was obtained the stereoisomer of carbomethoxymethyl-2- methallyl-2,4b-dimethyl 7 ethylenedioxy -1,2,3,4,4a, 4b,5,6,7,8,l0,10a-dodecahydrophenanthrene-4 01 having an M.P. of 138-139 C.

When the stereoisomer of l-carboxymethyl-Z-methallyl-2,4b dimethyl 7 ethylenedioxy 1,2,3,4,4a,4b,5, 6,7,8,10,IOa-dodecahydrophenanthrene 4 01 having an M.P. of 255-257 C. was used as starting material there was obtained the stereoisomer of l-carbomethoxymethyl- 2-methally1-2,4b-dimethyl-7 ethylene dioxy 1,2,3,4,4a, 4b,5,6,7,8,10,IOa-dodecahydrophenanthrene 4 01 having an M.P. of 157-158 C.

When the stereoisomer of l-carboxymethyl-Z-methallyl- 2,4b-dimethyl-7 ethylenedioxy l,2,3,4,4a,4b,5, 6,7,8,l0, 10a dodecahydrophenanthrene v4 01 having an M.P. of 216-220 C. was used as starting material there was obtained thestereoisomer of 1-carbomethoxymethyl-2-methallyl 2,4b dimethyl 7'- ethylenedioxy 1,2,3,4,4a,4b, 5,6,7,8,10,10a-dodecahydrophenanthrene 4 01 having an M.P. of 83-85 C. I i

A solution containing about 50 mg. of l-carbomethoxymethyl-Z-methallyl 2,4b dimethyl 7 ethylenedioxy- 1, a, ,8: 1 a 1 r 18 01 and about 15 mg. of p-t oluene sulfonic acid in about 3 ml. of acetone was heated under reflux for a period of about twenty minutes. The acetone reaction mixture was diluted with water and the resulting aqueous mixture extracted with chloroform. The chloroform extract was dried and evaporated to dryness to give l-carbomethoxymethyl-2-methyllyl 2,4b dimethyl 1,2,3,4,4a,4b,5,6,7,9, 10,lOa-dodecahydrophenanthrene-4-ol-7-one. When the stereoisomer of l carbomethoxymethyl 2 methallyl- 2,4b-dimethyl-7 ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10, 1()a-dodecahydrophenanthrene-4-ol having an M.P. of 137138 C. wasused as starting material, there was obtained the stereoisomer of 1 -carbomethoxymethyl-2 methallyl 2,4b dimethyl 1,2,3,4,4a,4b,5,6,7,9,10,10adodecahydrophenanthrene-4-ol-7-one having an M.P. of l33-134 C.

Example 9 A suspension of-4.15 g. of l-carboxymethyl-Z-methallyl-2,4b-dimethyl-7 ethylenedioxy 1,2,3 ,4,4a,4b,5,6,7, 8,10,10a-dodecahydrophenanthrene-4-ol and 8 g. of anhydrous potassium carbonate in 50 ml. of dry acetone containing 8 ml. of methyl iodide was stirred, in a looselystoppered flask, at room temperature for a period of about fifteen hours. The reaction solution was filtered thereby removing the precipitated potassium iodide and excess potassium carbonate. The acetone was evaporated from the filtered solution in vacuo, and the residual oil was dissolved in ether; the ethereal solution was washed twice with 10 mL-portions of water, driedover anhydroussodium sulfate, and the solvents evaporated. The residual oil was crystallized from ether and .dried to give substantially pure 1-carbomethoxymethyl-2-methallyl-2,4b dimethyl 7 ethylenedioxy l,2,3,4,4a,4b,5,6,7,8,10,10adodecahydrophenanthrene-4-ol.

In accordance with the foregoing experimental procedure and utilizing the stereoisomer of l-carboxymethyl- 2-methallyl 2,4b dimethyl 7 ethylenedioxy 1,2,3, 4,4a,4b,'5,6,7,8,10, 10a dodecahydrophenanthrene 4 01 having an M.P. of 216-220 C. as starting material,

there was obtained the stereoisomer of 'l-carbomethoxj methyl 2 methallyl 2,4b dimethyl 7 ethylene dioxy 1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenan-- thre'ne-4-ol having an M.P.of 8385 C.

Example 10 A solution of 350 mg. of l-carbomethoxymethyl-2- methallyl 2,4b dimethyl 7 ethylenedioxy 1,2,3,4,4a,-

4b,5,6,7,8,10,10a-dodecahydrophenanthrene 4 01 in 3.5

ml. of pyridine was added to the complex formed by evaporated. The residual oil was crystallized twice from ether to give substantially pure 1--carbomethoxymethyl-2- methallyl 2,4b dimethyl 7 ethylenedioxy 1,2,3,4,4a,. 4b,5,6,7,8,10,l0a-dodecahydrophenanthrene-4-one.

In accordance with the foregoing experimental procedure and utilizing as starting material the stereoisomer of 1 carbomethoxymethyl-Z-methallyl-2,4b-dimethyl-7- ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,1021 dodecahy drophenanthrene-4-ol having an M.P. of 138-139 C.-, there was obtained the stereoisomer of l-carbomethoxy: methyl 2 methallyl 2,4b dimethyl-7-ethylenedioxy- 1,2,3,4,4a,4b,5,6,7,8,l0,10a dodecahydrophenanthrenel one having an M.P. of -127 C.; when the stereo-; isomer of l-carbomethoxymethyl 2 -.methallyl-2,4b-di-. methyl .7 ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene-t-ol having an M.P. of 157- 158 C. was used as starting material there was obtained;

the stereoisomer .o f lecarbomethoxymethyl-z-methallylfij {4b dimethyl a 7 ethylenedioxy-1,2,3,4,4a,4b,5,6,7,8,10, lOa-dodecahydrophenanthrenel{one' having an M.P. of 14 141? 0; when the'stereoisomer of l-carbomethoxymethyl-2-methal-ly1-2,4b dimethyl 7 ethylenedioxy-1,2,3, 4,4a,4b,5,6,7,8,l0,10a do'decahydrophenanthreue 1 4 01 having an M.P. of 83-85 C. was used as starting material there was obtained the stereoisomer of l-carboniethoxymethyl 1 2 -'methallyl-2,4b-dimethyl-7-ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene-4-o'ne having an M.P.of '142146 C.

When the stereoisomer of 1-carboxymethyl-2-methallyl- 2,4b-di'mcthyl 7 ethylenedioxy-l,2,3,4,4a,4b,5,6,7,8,10- a-dodecahydrophenanthrene-4-ol having an M.P. of 234-235 C. was reacted with dia zomethane in ether in accordance with the procedure described in Example 8 hereinabove, and the resulting stereoisomer of l-carbomethoxymethyl 2 methallyl-2,4b-dimethyl-7-ethylenedioxy 1,2,3,4,4a,4b,5, 6,7,8,10,10a dodecahydrophenanthrerie=4-ol reacted with chromium trioxide-pyridine complex in accordance with'the procedure described in the present example there was obtained the stereoisomer of 1 carbomethoxymethyl 2 methallyl-2,4b-dimethyl-7- ethylenedioxy 1,2,3,'4,4a,4b,5,6,7,8,10,10a-dodecahydrophenanthrene-4-one having an M.P. of 155 C.

I Jpon heating together, under reflux, l-carbomethoxymethyl-2-methallyl-2,4b-dirnethyl 7 ethylenedioxy-l,2, 3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene-4-one and an acetone solution of p-toluene sulfonic acid, whereby the ethylenedioxy substituent is hydrolyzed without appreciably affecting the carbomethoxy ester grouping, there. is obtained l-carbornetho'xymethyl-1,2,3,4,4a,4b,5, 6,7,9,10,l0a-dodecahydroplienanthrene-4,7- dione.

Example 11 To a solution of 378. mg. of 1-carbomethoxymethyl-2- methallyl-2,4b-dimethy1 7- ethylenedioxy-l,2,3,4,4a,4b, 5,6,7,8,10,10a-dodecahydrophenanthrene-4-one in 3 ml. of dry, ether and 0.5 ml. of.dry benzene was added 254 mg. of osmium tetroxide. The resulting solution began to deposit in a few minutes a brown-black precipitate which can be recovered by filtration and dried to give the osmate ester of 1-carbomethoxymethyl-2-(beta, gamma-dihydroxyisobutyl)-2,4b-dimethyl-7-ethylenedioxy l,2,3,4,4a, 4b,5,6,7,8,10,10a dodecahydrophenanthrene-4-one. Insteadof isolating the osma'te ester, the reaction mixture was allowed to stand at room temperature for a period of 'one hour, and 18" ml. of ethanol was then added to the reaction mixture. A solution of 0.8 g. of anhydrous sodium sulfite in 9 ml. of water was added to the alcoholic reaction mixture, the resulting mixture was vigorously agitated for a period of about three minutes, and the precipitated osmium oxide removed by filtration. The filtered reaction solution was cautiously acidified with dilute acetic acid to'a pH of about 6, and the mildly acid aqueous solution was evaporated under reduced pressure to "an oil. Water was added to the oil, and the aqueous mixture was extracted with ether. The ether extract was washed with Water, dried over anhydrous sodium sulfate, and the ether evaporated. The residual crystalline material was crystallized from ethyl acetate to give l-carbomethoxymethyl 2 (beta,garnma-dihydroxyisobutyl)-2, 4b-dl-methyl 7 ethylenedioxy-l,2,3,4,4a,4b,5,6,7,8,l0, 10a-dodecahydrophenanthrene-4-one.

In accordance with the foregoing experimental procedure and utilizing as starting material the stereoisomer of 1 carbomethoxymethyl 2 methallyl-Z,4b-dimethyl-7- eth'ylenedioxy l,2,3,4,4a,4b,5,6, 7,8,10,10a dodecahydrophenanthrene-4-one having an M.P. of 125-127 C., there was obtained the stereoisomer of l-carbome thoxymethyl 2 (beta,gamma dih'ydroxyisobu'tyl) 2,4b dimethyl 7 ethylenedioxy-l,2,3,4,4a,4b,5,6,7,8,10,lOa-do decahydrophenan'threne-4-one having an M.P. of 172- 174 C.; when the stereoisomer of l-carbomethoxymethyl- 2-methal1y1-2,4b-dimethy1-7-ethylenedioxy 1,2,3,4,4a,4b,

5, ,7,8,10,10a-dodecahydrophehanthrene-kone having an M.P. of1 40 -l41 C. was used as starting material, there was obtained the stereoisomer of l-carbomethoxymethyl- 2-(beta,gamma dihydroxyisobutyl) 2,4b dimethyl-7- ethylenedioxy 1,2,3,4,4a,4b,5, 6,7,8,10,10a-dodecahydrophenanthrene-4-one having an M.P. of 142-155 C.; when the stereoisomer of 1-carbomethoxymethyI-Z-methallyl-Z, 4b-dimethyl 7- ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10, 10a-dodecahydrophenanthrene-4-one having an M.P. of 142-146 C. .was used as starting material, there was obtained the stereoisomer of l-carbomethoxymethyl-Z- (beta,gamma dihydroxyisobutyl)-2,4b-dimethyl-7-ethylenedioxy l,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrenel-one having an M.P. of l43147 C.

Upon heating together, under reflux, l-carbomethoxymethyl 2 (beta,gamma-dihydroxyisobutyl) 2,4b dimethyl 7 ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,1 0adodecahydrophenanthrene-4-one and an acetone solution. of p-toluene sulfonic acid, whereby the ethylenedioxy substituent is, hydrolyzed without appreciably affecting the carbomethoxy ester grouping, there is obtained 1- carbomethoxymethyl 2 (beta,gamma dihydroxyisobutyl)-2,4b-dimethyl 1,2,3,4,4a,4b,5,6,7,9,10,10a-dodecahydrophenanthrene-4,7-dione.

Example 12 To a solution of 400 mg. of l-carbomethoxymethyl-Z- (beta,g amma dihydroxyisobutyl) 2,4b dimethyl 7- ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene-4-one in 4 ml. of ethanol was added 1 ml. of pyridine and a solution of 350 mg. of periodic acid in 2 ml. of water. The resulting mixture was allowed to stand for a period of about six minutes at the end of which time the exothermic reaction which occurred was substantially complete. The reaction mixture was diluted with 20 ml. of water, and the aqueous mixture extracted with ether. The ether extract was washed with 5. ml. of water, dried over sodium sulfate, filtered and the ether. evaporated. The residual oil was crystallized from petroleum ether to give substantially pure l-carbomethoxymethyl-Z-acetonyl 2,4b dimethyl-7-ethylencdioxy l,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene-4-one.

In accordance with the foregoing experimental procedure and utilizing as starting material the stereoisomer of 1-carbomethoxymethyl-2-(beta,gamma-dihydroxyisobutyl)-2,4b-dimethyl-7-ethylenedioxy 1,2,3,4,4a,5,6,7,8, 10,10a-dodecahydrophenanthrene-4-one having an M.P.

of 172174 C., there was obtained the stereoisomer of: 1 carbomethoXymethyI-Z-acetonyl-2,4b-dimethyl-7-ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene-4-one which crystallized from ether in a crystalform having a M.P. of 108-10 9 C. and which crystallized from ethyl acetate-petroleum ether in a crystal rform having an M.P. of -95 C.; when the stereoisomer of l-carbomethoxyrnethyl-Z-(beta,gamma-dihydroxyisobutyl) -2,4b-dimethyl-7-ethylenedioxy 1,2,3,4,4a, 4b,5,6,7,8,10,lOa-dodecahydrophenanthrene-4-one having an M.P. of 142155 C. was used as starting material, there was obtained the stereoisomer of l-carbomethoxymethyl-2-acetonyl-2,4b-dimethyl-7-ethylenedioxy 1,2,3, 4,4a,4b,5,6,7,8,10,10a-dodecahydrophenanthrene 4-onc having an M.P. of 132-134 C.; when the stereoisomer of 1-carboxymethoxymethyl-2-(beta,gamma dihydroxyisobutyl)-2,4b-dimethyl-7-ethylenedioxy 1,2,3,4,4a,4b,5, 6,7,8,-10,10a-dodecahydrophenanthrene-4-one having an M.P. of 143-447 C. was used as starting material, there was obtained the stereoisomer of l-carbomethoxymethyl- 2-acetonyl 2,4b-dirnethyl-7-ethy1enedioxy 1,2,3,4,4a,4b,

5,6,7,8;10;10a-dodecahydrophenanthrenel-one having an- M.P. of 144 C.

Upon heating together, under reflux, l-carbomethoxy- .21 and an acetone solution of p-toluene sulfonic acid, there is obtained 1-carbomethoxymethyl-2-acetonyl-2,4b-dimethyl 1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene-4,7-one.

' Example 13 One gram of 1-carbomethoxymethyl-Z-methallyl-2,4b- ,dimethyl-7.-ethylenedioxy-1,2,3,4,4a,4b-,5,6,7,8,10,10a-dodecahydrophenanthrene-4-one was dissolved in 100 ml. of methanol. The resulting solution was cooled to a temperature of about 80 C. and a stream of ozonized oxygen containing one equivalent of ozone was passed, over a two-minute period, through the cold solution. The reaction mixture was warmed to a temperature of about C., and 10 ml. of water was added to the mixture followed by five grams of zinc and ml. of acetic acid. The resulting mixture was stirred for a period of about thirty minutes. Water and solid sodium carbonate were then added, the mixture was filtered, and the solvents were evaporated from the filtered solution in vacuo while maintaining the temperature of the solution below about 20 C. The residual material was extracted with ether and ether solution chromatographed on acid-washed alumina. Upon evaporation of the ether-petroleum ether eluate there was obtained l-carbomethoxymethyl-Z-acetonyl-2,4b-dimethyl 7 ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,10a d'odecahydrophenanthrene-4-one.

In accordance with the foregoing experimental procedure and utilizing as starting material the stereoisomer o-f 1-carbomethoxymethyl-2-methallyl-2,4b-dimethyl 7- ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,10a-dodecahydrophenanthrene-4-one having an M.P. of 125-127 C., there was obtained the stereoisomer of l-carbomethoxymethyl 2-acetonyl2,4b-dimethyl-7-ethylenedioxy-1,2,3, 4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene 4-one having an M.P. of 108109 C. when crystallized from ether.

Example 14 A solution of 506 mg. of l-carbomethoxymethyl-Z- acetonyl-2,4b dimethyl-7-ethylenedioxy-1,2,3,4,4a,4b,5, 6,7,8,10,10a-dodecahydrophenanthrene-4-one in benzene was distilled at room temperature until the volume of the solution was about ml. This procedure assured a dry solution. This dry solution was added to solid sodium methoxide. (The solid sodium methoxide was prepared by removing the excess methanol from 2.4 ml. of a 1 molar methanol solution of sodium methoxide by baking at 150 C. for thirty minutes in vacuo.) The mixture of the benzene solution of the hydrophenanthrene compound and the solid sodium methoxide was allowed to stand at room temperature for a period of about twenty minutes, at the end of which time a flocculent solid precipitated from the benzene solution. The resulting mixture was stirred at room temperature for a period of about fifteen hours. A mixture of cold water (0 C.) and ether was added to the reaction product and the resulting mixture was vigorously agitated. The aqueous phase was quickly separated and immediately acidified with an excess of an aqueous solution of sodium dihydrogen phosphate. The acidified aqueous solution was extracted with chloroform, and the organic extract was dried over anhydrous sodium sulfate, filtered, and the chloroform evaporated. The residual crystalline material was recrystallized from ethyl acetate-ether, and from ethanol, to give A -3-ethylenedioxy-11,16,20- triketo-pregnene.

In accordance with the foregoing experimental procedure and utilizing as starting material the stereoisomer of 1 carbomethoxymethyl-2-acetonyl-2,4b-dimethyl 7- ethylenedioxy-l,2,3,4,4a,4b,5,6,7,8,10,l0a dodecahydrophenanthrene-4-one having an M.P. of 132-134 C., there was obtained the stereoisomer of A -3-ethylenedioxy-11,16,20-triketo-pregnene having an M.P. of 154- 156 C.; when the'stereoisomer of l-carbomethoxymethyl-2-acetony1- 2,4b-dimethy1-7ethylenedioxy-1,2,3, ,10a dodecahydrophenanthrene-4-one having, when crystallized from ether, an M.P. of 108- 109 0., there was obtained the stereoisomer of A. -3 ethylenedioxy ll,l6,20-triketo-pregnene having an M.P. ot' 226-229 (3.; when the stereoisomer of l-carbomethoxymethyl-2-acetonyl 2,4b-dimethy1-7 ethylenedioxy-l, 2,3,4,4a,4b,5,6,7,8,10,10a dodecahydroxyphenanthrene- 4-one, having an M.P. of 144 C. was used as starting material, there was obtained the stereoisomer of A -3- ethylenedioxy-l1,16,20-triketo-pregnene having an M.P. of 213215 C. I

Upon heating together, under reflux, A -3-ethylene dioxy-11,16,20-triketo-pregnene-and an acetone solution of p-toluene sulfonic acid (substantially in accordance with the procedure described in Example 1 hereinabove), there was obtained A -3,l1,16,20-tetraketo-pregnene; when the stereoisomer of A -3-ethylenedioxy-11,16,20- triketo-pregnene having an M.P. of 154-156" C. is used as starting material in this procedure, there was obtained the stereoisomer of A -3,11,16,20-tetraketo-pregnene having an M.P. of 187-189 C.

Example 15 To a solution of 295 mg. of A -3-ethylenedioxy-1Ll6- ZO-triketo-pregnene in 3.7 ml. of pyridine was added 370 mgof p-toluenesulfonyl chloride. The resulting mixture was allowed to stand at room temperature for about twenty-two hours. At the end of this period 2.3 ml. of saturated aqueous sodium bicarbonate solution were added to the cooled reaction mixture, thereby neutralizing the pyridine hydrochloride formed by the reaction as well as the excess p-toluenesulfonyl chloride. The aqueous pyridine mixture was agitated at roomtemperature for a period of about fifteen minutes during which time a crystalline product precipitated. Benzene was added to the reaction mixture, the mixture was poured onto ice, and dilute aqueous hydrochloric acid was added until the mixture was just acid. The organic layer was rapidly separated, washed with water, and with aqueous sodium bicarbonate solution. The washed organic layer was dried over sodium sulfate, and evaporated to dryness in vacuo. The residual material was recrystallized from benzene-petroleum ether-ether. and then chromatographed on acid-washed alumina. The material obtained from the 1:1 petroleum ether-ether eluate was recrystallized from benzene-ether to give substantially pure A -3- ethylenedioxy 16-p-toluenesulfonoxy-11,20-diketo-pregnadiene. i

In accordance with the foregoing experimental procedue and utilizing as starting material the stereoisomer of A -3-ethylenedioxy-11,16,20-triketo-pregnene having an M.P.154156 0., there was obtained the stereoisomer of A -3-ethyIenedioXy-l6-p-toluenesulfonoxylLZO-diketO-pregnadiene having an M.P. of 19920l C.; when the stereoisomer of A -3-ethylenedioxy-1L16, ZO-triketo-pregnene having an M.P. of 226-229 C. was usedas starting material, there was obtained the stereoisomer of A -3-ethylenedioxy-16-p-toluenesulfonoxy- 11,20-diketo-pregnadiene having an M.P. of 189-l90 C.; when the stereoisomer of A -3-ethy1enedioxy-l1,16, ZO-triketo-pregnene having an M.P. of 213-215 C. was used as starting material, there was obtained the stereoisomer of A -3-ethylenedioxy-16-p-toluenesulfonoxyll,20-dilteto-pregnadiene having an M.P. of 198-200" C. 7 Upon heating together, under reflux, A -3-ethylenedioxy -16 -p toluenesulfonoxy-l1.20-diketo-pregnadiene and an acetone solution of p-toluene sulfonic acid, there is obtained A -16-p-toluenesulfonoxy-3,ll,ZO-triketm pregnadiene.

Example 6 7 To a solution of 52 mg. of A -3-ethylenedioxy-16-ptoluenesulfonoxy-l1,20-diketo-pregnadiene in 10 ml. of benzene was added 2 g. of palladium catalyst (5% Pd ,on BaCO and the mixture was shaken at room temperature in contact withhydrogen under a pressure of about forty pounds per square inch. After about two hours, an additional 0.8 g. of catalyst was added and, after four more hours, another 0.8 g. of catalyst was added to the hydrogenation mixture. The resulting mixture was shaken for an additional fifteen hour period at room temperature in contact with hydrogen at a pressure of forty pounds per square inch. The reaction mixture was filtered thereby removing the catalyst and the benzene was evaporated from the filtered solution in vacuo. The residual material was treated with ether and the crystalline product thus obtained was recrystallized from ether-petroleum ether-ether to give substantially pure A -3 -'ethylenedioxy-l 1,20-diketo-pregnene.

In accordance with the foregoing experimental procedure and utilizing as starting material the stereoisomer of A -3-ethylenedioxy-16-p-toluenesulfonoxy-l1,20-diketo-pregnadiene having an M.P. of l99201 C. (which was prepared using the stereoisomer of A -3-ethylenedioxy-l1,16,20-triketo-pregnene of M.P. 154-l56 there was obtained the stereoisomer of A -3-ethylenedioxy-l1,20-diketo-pregnene having an M.P. of 181-1825 C.; when the stereoisomer of A -3-ethylenedioxy-16-ptoluenesulfonoxy 11,20 diketo pregnadiene having an M.P. 015189-190 C. was used as starting material, there was obtained the stereoisomer of A -3-ethy1enedioxy- 11,20-diketo-pregnene having an M.P. of 142-145 C.; when the stereoisomer of A -3-ethylenedioxy-l6-p-toluenesulfonoxy-l1,20-diketo-pregnadiene having an M.P. of 198-200 C. (prepared, in turn, from the stereoisomer of A -3-ethylenedioxy-l1,16,20-triketo-pregnene of M.P. 213-215 C.) there was obtained the stereoisomer of A B-ethyIenedioxy-l-1,20-pregnene, having an M.P. of 171- 172 C.

Each of the three stereoisomers of A -3-ethylenedioxy- 11,20-diketo-pregnene, when prepared as described in the present example, are obtained in the form of racemates; i.e. dl-A -3 -ethylenedioxy-l1,20-diketo-pregnene of M.P. 181-1825 C.; dl-A -3-'ethylenedioxy-1 1,20-diketo-pregnene of M.P. 142-145 C.; and dl-A -3-ethylenedioxyl1,20-diketo-pregnene of M.P. 171-172 C.

Example 17 To a solution of 20mg. of A -3-ethylenedioxy-11,20-diketo-pregnene in 1 ml. of tetrahydrofuran was added 0.5

.ml. of 3 N aqueousperchloric acid solution. The reaction mixture was allowed to stand at room temperature for a period of approximately three and one-half hours. The solvents were evaporated from the reaction mixture in vacuo, and the residual material was extracted with chloroform. The chloroform extract was dried over sodium sulfate, and the solvent evaporated from the dry chloroform extract in vacuo. The residual material was recrystallized from ether to give A -3,11,20-triketo-pregnene.

In accordance with the foregoing experimental procedure and utilizing the racernate of A -3-ethylenedioxy- 11,20-diketo-pregnene having an M.P. of 181-182.5 C. as starting material, there was obtained the racemate of A -3,11,20-diketo-pregnene having an M.P. of 175.5- 176.5 C.; when the racemate of A -3-ethylenedioxy- 11,20-diketo-pregnene having an M.P. of 142-145 C. was used as startingmaterial, there was obtained the racemate of- A -3,11,20-triketo-pregnene having an M.P. of l53-l58 Cz; when the racemate of A -3-ethylenedioxy-l1,20-diketo-pregnene having an M.P. of 171-172 C. was used as starting-material, there was obtained the racemate of A -3,l1,20-triketo-pregnene having an M.P. of 153 C. and 168 C. (dimorphic).

The racemate of A .-3,11,20-triketo-pregnene having an M.P. of l75.'5-176.5 C. possesses the stereoisomeric configuration characteristic of the naturally occurring steroid hormones such as progesterone; we refer to this racemate (M.P. 175.5-176.5 C.) as dl-ll-keto-progesterone.

Example 18 To a solution of 222 mg. of l-ethoxyethinyl-Z-methallyl 2,4b dimethyl 7 ethylenedioxy 1,2,3,4,4a,4b,5, 6,7,8,10,10a dodecahydrophenanthrene 1,4 diol (M.P. 108-111 C.) in 2 ml. of tetrahydrofuran was added 0.008 ml. of concentrated sulfuric acid. After three minutes at room temperature, an excess of sodium carbonate solution was added to the reaction mixture and the tetrahydrofuran was evaporated. The organic material which separated was extracted into ether; the ether extract was washed once with water, dried over magnesium sulfate and the ether was evaporated. The residual oily material was dissolved in benzene and chromatographed on acid-washed alumina. The adsorbate was eluted with mixtures of ether and petroleum ether; upon evaporation of the 2:8 ether-petroleum ether eluate there was obtained 1 carbethoxymethylene 2 methallyl 2,4b dimethyl- 7 ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrenet-ol which melted at -120 C. after purification by recrystallization from ether-petroleum ether.

Example 19 A suspension of 60 mg. of l-carbethoxymethylene-Z- methallyl 2,4b dimethyl 7 ethylenedioxy 1,2,3,4,4a, 4b,S,6,7,8,10,10a dodecahydrophenanthrene-4-ol (M.P. 105-120 C.) in 5 ml. of methanol and 5 ml. of water containing 0.5 g. of potassium carbonate and 1 ml. of l N potassium hydroxide was heated under reflux for three hours. The methanol was evaporated under reduced pressure and the aqueous residue was diluted with water and extracted with ether to remove any neutral material. The aqueous solution was acidified with excess sodium dihydrogen phosphate and the acidifiedmixture was extracted with chloroform. After drying over magnesium sulfate, the chloroform extract was filtered and evaporated to dryness under reduced pressure. The residual material was crystallized from benzene-petroleum ether to give substantially pure l-carboxymethylene- 2 methallyl 2,4b dimethyl 7 ethylenedioxy 1,2,3, 4,4a,4b,5,6,7,8,l0,l0a dodecahydrophenanthrene 4 ol melting at 174-180 C.

Treatment of the 1-carboxymethylene-2-methallyl-2,4bdimethyl 7 ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,l0, 10a-dodecahydrophenanthrenel-ol with a slight excess of diazomethane in ether solution gave l-carbomethoxymethylene 2 methallyl 2,4b dimethyl 7 ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,1021 dodecahydrophenanthrene-4-ol, M.P. 134-135 C.

Oxidation of the l-carhomethoxymethylene-Z-methallyl 2,4b dimethyl 7 ethylenedioxy l,2,3,4,4a,4b, 5,6,7,8,10,10a dodecahydrophenanthrene 4 ol (M.P. 134-135 C.) with chromic anhydride and. pyridine gave a steroisomer of 1-carbomethoxymethylene-2- methallyl 2,4b dimethyl 7 ethylenedioxy 1,2,3,4, 4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene 4 one M.P. ISO-153 C.

Example 20 A solution of 229 mg. of l-carboxymethylene-Z-methallyl 2,4b dimethyl 7 ethylenedioxy 1,2,3,4,4a,4h, 5,6,7,8,10,l0a-dodecahydrophenanthrene-4-ol in 5 ml. of ether was added to a solution of 40 mg. of lithium in 10 ml. of liquid ammonia at 78 C. The liquid ammonia reaction mixture was allowed to warm to -40 C. with stirring. After twenty minutes the blue lithium color was discharged. An additional 40 mg. of lithium was added and the mixture was stirred at 40 C. for an additional hour. The excess ammonia was evaporated from the reaction mixture at room temperature and 5 ml. of'ether was added. Etheyl acetate was then added cautiously to destroy the excess lithium. Water was added to the mixture and the ether layer was discarded. The

alkaline aqueous layer was acidified with. excess sodium dihydrogen phosphate and the acidic product was extracted with chloroform. The chloroform extract was washed with water, dried over magnesium sulfate, filtered, and the chloroform evaporated under reduced pressure. Crystallization of the residue from benzene gave substantially pure 1-carboxymethyl-2-methallyl-2,4bdimethyl 7 ethylenedioxy l,2,3,4,4a,4b,5,6,7,8,l0,10a dodecahydrophenanthrene-4-ol melting at 195-197 C.

Oxidation of the l-carboxymethyl-2-methallyl-2,4bdimethyl 7 ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,10adodecahydrophenanthrenel-ol with chromic anhydride and pyridine gave l-carboxymethyl-2-methallyl-ZA-b-di methyl 7 ethylenedioxy l,2,3,4,4a,4b,5,6,7,8,10,10adodecahydrophenanthrene-4-one. l

Treatment of the 1-carboxymethyl-Z-methallyl-2,4bdimethyl 7 ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,10adodecahydrophenanthrene-4-ol with a slight excess of diazomethane in ether solution gave l-carbomethoxymethyl 2 methylallyl 2,4b dimethyl 7 ethylenedioxy l,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene-4-ol; M.P. l42144 C.

Example 21 One gram of l-carboxymethyl-Z-methallyl-2,4b-dimethyl 7 ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,10adodecahydrophenanthrene-4-one was dissolved in 30 ml. of water containing 1.1 ml. of 4 N aqueous sodium hydroxide and 10 ml. of ethanol. One gram of sodium borohydride was added, and the solution was allowed to stand at room temperature overnight. One more gram of sodium borohydride was added, and the solution was boiled 1 /2 hours. It was poured into ice water, and acidified with excess sodium dihydrogen phosphate. The acid mixture was extracted twice with chloroform, the combined extracts were evaporated, and the amorphous residue was crystallized from ether. Recrystallization from ethyl acetate and from tetrahydrofuran-petroleum ether afforded 1 carhoxymethyl 2 methallyl-2,4b-dimethyl 7 ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,10adodecahydrophenanthrene-4-ol, M.P. 167-169 C.

Example 22 To a solution of 20.7 g. of l-ethoxyethinyl-Z-allyl- 2,4b dimethyl 7 ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8, 10,10a-dodecahydrophenanthrene-l-ol-4-one (M.P. 83.5- 85.0 C.) in 165 ml. of absolute tetrahydrofuran was added 12.0 ml. of 10% aqueous sulfuric acid. The temperature of the solution was maintained at a temperature of 28-30 C. for a period of three and one-half hours. After the first 45 minutes had elapsed, there was added 0.17 ml. of pyridine, and the reaction mixture was stirred for the remaining time. The reaction was quenched by the addition of excess aqueous sodium bicarbonate. The organic solvent was distilled off in vacuo and the remaining material extracted with ether. The extract was washed with water, dried over magnesium sulfate, and concentrated to dryness. Chromatography of the oilyresidue over 800 g. of alkaline alumina yielded 1-carboethoxymethylene-2-allyl-2,4b dimethyl-7 ethylenedioxy-1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene-4-one, an amorphous solid. Further elution provided 1-carboethoxymethyl-Z-allyl-Z,4b-dimethyl- 7-ethylenedioxy l,2,3,4,4a,4b,5,6,7,8,l0,10a dodecahydrophenanthrene-l-ol-4-one, M.P. 99-101 C.

In accordance with the above method, and using the stereoisomer of 1-ethoxyethinyl-2-allyl-2,4b-dimethyl-7- ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene-l-ol-4-one melting at l59160 0., there was obtained the stereoisomer of l-carboethoxymethyl-Z- allyl-2,4-dimethyl-7-ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8, 10,1Oa-dodecahydrophenanthrene 1 o1 4 one, M.P. 101C.'

Example 23 A solution of 175 mg. of l-carboethoXymethylene-Z- allyl-2,4b-dimethyl 7 ethylenedioxy-1,2,3,4,4a,4b,5,6,7, 8,l0,10a-dodecahydrophenanthrene-4-one in 2.9 ml. of methanol was treated with a solution of 0.37 g. of potassium carbonate in 2.7 ml. of water. The resulting mixture was heated to boiling under reflux for a period of two and one-half hours. The methanol was removed under reduced pressure and the aqueous solution acidified with excess sodium dihydrogen phosphate. An ether extraction was made of the solution, and the extract washed with water, dried over magnesiumsulfate, and concentrated in vacuo. The resulting oil crystallized from petroleum ether and was recrystallized from benzene-petroleum ether to give pure 1-carboxymethylene-2-a1lyl-2,4bdimethyl-7-ethylenedioxy-1,2,3,4,4a,4b,5,6,7,8,10,10a d0- decahydrophenanthrene-4-one, having a melting point of 163-164 C.

Example 24 A suspension of 14.2 g. of l-carboxymethylene-Z-allyl- 2,4b-dimethyl -7- ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,

Example 25 1-carboxymethylene-2-allyl-2,4b-dimethyl-7-ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene-4-one (15 g. of amorphous material) was added to one liter of anhydrous ammonia cooled to a temperature of -'60 C. followed by the addition of 15 g. of metallic potassium. There was then introduced 50 ml. of anhydrous isopropanol over a period of five minutes. The mixture was stirred until the reaction was over as evidenced bythe disappearance of the blue color charac teristic of metallic potassium in liquid ammonia. The ammonia was allowed to evaporate overnight. The remaining solution was then concentrated almost to dryness under reduced pressure. Two hundred milliliters of water were added followed by addition of a solution of 70 g. of sodium dihydrogen phosphate and 50 g. of phosphoric acid in 500 ml. of water. The crystalline material thus obtained was filtered and washed thoroughly with water, yielding l-carboxymethyl-2-allyl-2,4b-dimethyl-7-ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,10a dqdecahydrophenanthrene-4-ol, M.P. 235 .5236.-0 C.

Example 26 To a solution of 10.90 g. of l-carhoxymethyl-Z-allyl- 2,4b dimethyl 7 ethylenedioxy 1,2,3,4,4a,4b,5,6,7, 8,10,10a dodecahydrophenanthrene -4- 01 (M .P. 235 .5 236.0 C.) in one liter of absolute tetrahydrofuran was added an excess of diazomethane in ether. After standing overnight at room temperature, the solvents were removed by evaporation, and the residual material crystallized from ethyl acetate-petroleum ether to give substantially pure 1-carhomethoxymethyl-Z-allyl-Z,4b-dimethyl-7- ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene-4-ol, M.P. 113-115 C. Recrystallization of this material from aqueous methanol gave a sec- 0nd crystalline modification M.P. l30-132 C.

Example 27 A mixture of 15.80 g. of 1-carboxymethyl- 2 ally1-2,4b= dimethyl -'7 ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,10:

27 dodecahydrophenanthreneA-ol and 40 g. of anhydrous potassium carbonate in 450 ml. of acetone and 40 ml. of methyl iodide was stirred at room temperature for 42 hours. The solvent was then distilled oil under reduced pressure and the residue treated with 100 ml. of water. The mixture was then extracted with chloroform, the extract washed with water, dried over magnesium sulfate, and concentrated to dryness in vacuo. The residual oil was taken up in a small volume of methanol and crystallized by addition of water, to give substantially pure 1- carbomethoxymethyl -2- allyl-2,4b-dimethyl-7-ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene-4-o1.

Example 28 A solution of 9.35 g. of 1-carbomethoxymethyl-Z-allyl- 2,4b dimethyl 7 ethylenedioxy 1,2,3,4,4a,4b,5,6,7, 8,10,10a-dodecahydrophenanthrenel-ol in 100 ml. of pyridine was added to the complex formed by adding 10 g. of chromium trioxide to 100 ml. of pyridine. After standing at room temperature overnight, the resulting mixture was diluted with an equal volume of water. The solution was then extracted with ether, and the extract washed with water, dried over magnesium sulfate, and concentrated to about 100 ml. One hundred milliliters of methanol were then added followed by addition of 500 ml. of water. The material which crystallized was filtered and dried to give l-carbomethoxymethyl 2 allyl 2,4b dimethyl 7 ethylenedioxy- 1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene 4-one crystallized; M.P. IDS-109 C.

Example 29 To a solution of 400 mg. of l-carbomethoxymethyl-2- allyl 2,4b dimethyl 7 ethylenedioxy 1,2,3,4,4a,4b, 5,6,7,8,10,10a-dodecahydrophenanthrene-4-one in 4 ml. of anhydrous ether was added 280 mg. of osmium tetroxide. The resulting mixture was stirred at room temperature for 45 minutes. To the mixture was added 20 ml. of ethanol and a solution of 1.7 g. of sodium sulfite in 11 ml. of Water. The solution was shaken for 20 minutes and then filtered. The filtrate was concentrated to about 10 ml. and extracted with chloroform. The extract Was washed with water, dried over magnesium sulfate, and concentrated to dryness in vacuo. Crystallization of the residue from benzene-petroleum ether gave 1-carborneth0xymethyl-2-(beta, gammadihydroxypropyl) 2,4b dimethyl 7 ethylenedioxy 1,2, 3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene 4- one, M.P. 163-164 C. Acidification of the aqueous layer from the chloroform extraction with excess sodium dihydrogen phosphate and extraction with chloroform followed by washing the extract with water, drying over magnesium sulfate, and concentrating to dryness in vacuo, provided l-carbomethoxymethyl-2-(beta, gamma, dihyhydroxypropyl) 2,4b dimethyl 7 ethylenedioxy- 1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene- 4-one, which after recrystallization from pyridine-petroleum ether decomposed at 228 C.

Example 30 Two hundred milligrams of l-carboethoxymethyl-Z- methallyl 2,4b dimethyl 7 ethylenedioxy 1,2,3,4, 4a,4b,5,6,7,8,10,10a dodecahydrophenanthreue 1 ol- 4-one in ml. of acetone were treated with 5 drops of hydrochloric acid and heated under reflux twenty minutes. The product was crystallized from ether to give 1 cnrbomethoxymethyl 2 methallyl 2,4b dimethyl- 1 ,2,3,4,4a,4h,5,6,7,9,10,10a dodecahydrophenanthrene- 1-ol-4,7-dione, M.P. 122-124. C.

Example 31 Three hundred milligrams of l-carboethoxymethyl-Z- methallyl 2,4b dimethyl 7 ethylenedioxy '1,2,3,4, 4a,4b,'5,6,7,8,10,10a- -.dodecahydrophenanthrene 1 o1 4-one were heated in 10 ml. of 2 N potassium carbonate in 50% aqueous methanol under reflux for seven hours. The methanol was removed in vacuo and the resulting alkaline solution was washed with ether. The washed alkaline solution was then acidified with excess sodium dihydrogcn phosphate followed by extraction with chloroform, drying and concentration to give crystalline 1- carboxymethyl 2 methallyl 2,4b dimethyl 7- ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,1021 dodecahydrophenanthrene-1-ol-4-one after crystallization from ethyl acetate; M.P. 213-215 C. This compound was heated for a short while in acetone and a trace of hydrochloric acid. Dilution with water gave l-carboxymethyl-Z-methallyl 2,4b dimethyl 1,2,3,4,4a,5,6,7,8,10,10a do decahydrophenanthrene-1-o1-4,7-dione; M.P. 205210 C. (dec.).

Example 32 The stereoisomer of l-carboethoxymethylene-Z-methallyl 2,4b dimethyl 7 ethylenedioxy 1,2,3,4,4a,4b, 5,6,7 ,8,10,10a dodecahydrophenanthrene 4 one (M.P. 94-96 C.) was hydrolyzed as in Example 30 to give the stereoisomer of l-carboethoxymethylene-Z-methallyl-Z,4bdimethyl 1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene-4,7-dione; M.P. 111-112 C.

Example 33 The stereoisomer of 1-carboxymethylene-Z-methallyl- 2,4b dimethyl 7 ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8, 1.0,10a-dodecahydrophenanthrene-4-one (M.P. 203-205 C.) was treated with diazomethane in ethyl ether to produce the corresponding stereoisomer of l-carbomethoxymethylene 2 methallyl 2 ,4b dimethyl 7 ethylenedioxy 1,2,3,4,4a,5,6,7,8,10,10a dodecahydrophenanthrenel-one; M.P. 152153.5 C.

Example 34 Treatment of 1-carbcmethoxymetl1yl-2-methallyl-2,4bdimethyl 7 ethylenedioxy 1,2,3,4,4a.,4b,5,6,7,8,10,10adodecahydrophenanthrene-4-ol (M.P. 157158 C.) with acetyl chloride in pyridine gave l-carbomethoxyrnethyl-Z- methallyl 2,4b dimethyl 4 acetoxy 7 ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene; M.P. 140-141 C.

Treatment of l-carbomethoxymethyl-Z-methallyl-2,4bdimethyl 7 ethylenedioxy l,2,3,4,4a,4b,5,6,7,8,10,10adodecahydrophenanthrene-4-ol (M.P. 83-85 C.) with acetyl chloride in pyridine gave l-carbomethoxymethyl-Z- methallyl 2,4b dimethyl 4 acetoxy 7- ethylenedioxy- 1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene; M.P. -126 C.

Treatment of 1-carboxymethylene-Z-methallyl-2,4b-dimethyl 7 ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,10adodecahydrophenanthIene-4-ol (M.P. 211-214 C.) with acetyl chloride in pyridine gave 1-carboxymethylene-2- methallyl 2,4b dimethyl 4 acetoxy 7 -ethylenedioxy- 1,2,3,4,4a,4b,5,6,7,8,10,102. dodecahydrophenanthrene; M.P. 125-126 C.

Example 35 One quarter milliliter of 10% sulfuric acid was added to a solution of mg. of 1-ethoxyethinyl-2-methallyl- 2,4b dimethyl 7 ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8, 10,10a-dodecahydrophenanthrene-1-ol-4-one (M.P. of 159161 C.) in 4 ml. of tetrahydrofuran. After seven hours at room temperature the reaction mixture was poured into excess sodium bicarbonate solution and the tetrahydrofuran removed in vacuo. The product was extracted with ether and chromatographed over 4.5 g. of alkaline'alumina. With 7:3 petroleum etherzether there was eluted 1 -carboethoxymethyl-Z-methallyl-2,4b-dimethyl 7 ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,10adodecahydrophenanthrene-1-o1-4-one. After recrystallization from petroleum ether the crystalline product had a melting point of 118-1 19 C.

29 Example 36 0.9 cc. of ethancdithiol was added to a cooled mixture of sulfate and .9 g. of 1-carbomethoxymethyl-Z-methallyl- 2,4b dimethyl 4,7 diketo 1,2,3,4,4a,4b,5,6,7,9,10, 10a-dodecahydrophenanthrene. After standing at room temperature for 3 days the reaction mixture was extracted with ether. Evaporation of the ethereal extract gave a crystalline residue which, upon recrystallization, from A solution of 4 g. of 2-carbornethoxymethyl-Z-methallyl 2,41) dimethyl-1,2,3,4,4a,4b,5,6,7,9,10,10a-dodecahydrophenanthrene-4,7-dione in 15 ml. of dioxane was treated with 4 g. of fl-mercaptoethanol, followed by the addition of 5 g. of freshly fused zinc chloride and 5 g. of anhydrous sodium sulfate. The solution was cooled initially in ice and then allowed to stand at room temperature for 3 days. After dilution with water, the reaction mixture was extracted with chloroform. The chloroform extract was washed with water until neutral, dried and the solvent evaporated in vacuo. The residual material was recrystallized from ether to give substantially pure l-carbornethoxymethyl 2 methallyl 2,4b -dimethyl 1,2,3, 4,4a,4b,5,6,7,8,10,10a 4 dodecahydrophenanthrene 4,7 dione-7-ethylenehemithioketal. The hemithioketal, prepared according to the foregoing procedure, exhibits substantially no absorption in the ultraviolet.

The parent ketone may be reformed by treatment with acetone-hydrochloric acid.

The 1-ethoxyethinyl-2-methallyl-2,4b-dimethyl-7-ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene-l-ol-4-one used as starting material in Example 1 hereinabove can be prepared from 7 -keto-4b-methyl-1,2, 3,4,4a,4b,5,6,7,9,10,la dodecahydrophenanthrene 1,4- diol (the preparation of which is described in Patent No. 2,617,828, issued November 11, 1952), in accordance with the following procedure:

Into a 5 liter flask equipped with a stirrer, a 1 liter dropping funnel and a sidearm with condenser attached in distilling position, were placed 38.9 g. (0.155 mole) of 4b methyl l,2,3,4,4a,5,6,7,9,10,10a dodecahydrophenanthrene-1,4-diol-7-one. 40 cc. (0.645 mole) of glycol, 2,500 cc. of ethylene dichloride and 0.4 g. (0.002 mole) of p-toluene sulfonic acid. This mixture was set stirring. Enough heat was applied to distill off 3 liters of the azeotrope of the solvent and water, formed as a by-product, during a 3-hour period. During this time an additional 1,500 cc. of ethylene dichloride was added to keep the reactants in solution. After 3 hours the reaction mixture was cooled and thoroughly shaken with 50 cc. of an aqueous 1 Normal potassium bicarbonate solution. The aqueous carbonate layer was drawn off and twice extracted with ethylene dichloride. All three ethylene dichloride extracts were then combined, dried over anhydrous magnesium sulfate and concentrated. This concentrate was taken up in 1 liter of acetone and concentrated until crystals just began to come out. Filtration of the cold acetone gives the crude crystalline product 4b-methyl- 7 ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene-1,4-diol which can be further purified by recrystallization from acetone. The pure product melts at 189 C.

Eighty-six and five tenths grams (0.294 mole) of 4bmethyl 7 ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,10adodecahydrophenanthrene-1,4-diol was dissolved in 2,130 g. (2,250 cc.) (21.7 moles) of cyclohexanone, and 2,250 cc. of benzene. To this solution was added 86.5 g. (0.424 mole) of aluminum isopropoxide, and the whole was then 30' set to reflux for 12 hours. At the end of thistime 25 cc. of water was added. The coagulated aluminum hydroxide thus formed was filtered off. The filtrate was concentrated and dried in vacuo, leaving a residue which, on trituration with petroleum ether, gave the crude crystalline product 4b-methyl-7-ethylenedioxy-l,2,3,4,4a,4b,5,6, 7,8,l0,lOa-dodecahydrophenanthrene-4-ol-l-one. It can be purified by recrystallization from acetone and melts at 219-220 C.

To 10.0 g. of 4b-methyl-7-ethylenedioxy-l,2,3,4,4a,4b, 5,6,7,8,10,l0a dodecahydrophenanthrene-4-ol-l-one dissolved in ml. of benzene and 70 ml. of t-butyl alcohol was added, at reflux temperature, 1.5 equivalents of 1 M potassium t butoxide in t-butyl alcohol, and 20 ml. of a 1:1 solution of methyl iodide in benzene. After 30 minutes of refluxing, the solution was quenched with water, concentrated in vacuo, and the concentrate extracted with CHCl The CHCl extract was dried and the solvent removed in vacuo. Fractional crystallization of the crystalline residue from ethyl acetate, yielded the desired product, 2,4b-dirnethyl-7-ethylenedioxy-l,2,3,4,4a,4b,5,6, 7,8,10,10a dodecahydrophenanthrene-4-ol-l-one, M.P. 189-192" C. l

A solution of 3.12 g. of 2,4b-dimethyl-7-ethylenedioxy- 1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrenel-one-4-ol (M.P. 189-192 C.) in 30 cc. of pyridine was combined with 3.1 g. of chromium trioxide in 30 cc. of pyridine. The reaction flask was stoppered, the contents mixed thoroughly and allowed to stand at room tempera ture overnight. The reaction mixture was poured into water and extracted with three portions of benzene-ether (1: 1) with filtration through diatomaceous earth to break the emulsions. After washing with water, the combined organic solution was dried over anhydrous magnesium sulfate and concentrated with final drying of the residue under vacuum. Crystallization from ether gave crystalline 2,4b-dimethyl 7 ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,l0, l0a-dodecahydrophenanthrene-1,4-dione M.P. -145 C. Chromatography over alumina and elution with petroleum ether-ether (8:2) gave two purified isomers, M.P. -136 C. and 152-l53 C.

Agqlution of 16.0 g. of crude 2,4b-dimethyl-7-ethylenedioliyv 1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthreire-lA-dione (M.P. 130-145 C. and consisting of amixture of isomers M.P. 135-136 C. and 152-l53 C.) in 190 cc. of benzene was concentrated to 160 cc. to insure dryness. The solution was then placed under nitrogen, and treated successively with 16.0 cc. of methallyl iodide and 70 cc. of tertiary butyl alcohol containing 2.31 g. of dissolved potassium. After standing at room temperature for three hours, the mixture was poured into ether, the ethereal solution washed with water, concentrated to dryness and purified by chromatography on either acid washed or alkaline alumina, the product being eluted with petroleum ether-ether mixtures. Pure 2,4b dimethyl-Z-methallyl 7 ethylenedioxy 1,2,3,4,4a,4b,- 5,6,7,8,l0,10a dodecahydrophenanthrene-l,4-dione was obtained, M. P.108109 C.

Another isomeric form of this compound having a melting point of 138-139 C. was also recovered from the chromatographic column.

A solution of ethyl magnesium bromide (0.1526 m.) was prepared in the usual manner from 3.7 g. of magnesium and excess ethyl bromide in 100 ml. of dry ether. A solution of 11.74 g. of ethoxyacetylene (0.165 In) diluted with dry ether to a total volume of 40 ml. was added gradually to the ethyl Grignard and stirred until the evolution of ethane ceased. 120 ml. of dry benzene was added to dissolve the ethoxyacetylene magnesium bromide.

A solution of 27 g. of dry 2,4b-dirnethyl-2-methallyl-7- ethylenedioxy-1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene-l,4-dione (stereoisomer of M.P. 108-l09 C.) in ml. of dry benzene was added rapidly to the stirred Grignard solution. After standing at room temperature for two hours, the reaction mixture was decomposed by pouring into ice-water. Enough saturated aqueous ammonium chloride was added to break the emulsion which formed. The benzene-ether layer was separated and washed once with water. The aqueous layer was extracted again with 500 ml. of a 1:1 benzeneether solution which, after one water wash, was combined with the original extract. After drying over anhydrous sodium sulfate and removal of the latter by filtration, the solvents were distilled in vacuo. rom a solution of the residual oil in ether were obtained crystals of the stereoisomer of 1-ethoxyethinyl-2,4b-dimethyl-2-methallyl-7-ethylenedioxy l,2,3,4,4a,4b,5,6,7,8,l0,lOa-dodecahydrophenanthrene-l-ol-4-one having an M.P. of 133- 134 C.

By using a stereochemical modification of the above starting material, M.P. 138l39 C., and treating as above described, there was obtained the stereochemical modification of 1-ethoxythinyl-Z,4b-dimethyl 2 methallyl 7 ethylenedioxy-l,2,3,4,4a,4b,5,6,7,8,10,10a-dodecahydrophenanthrene-1-ol-4-one having an M.P. of 13 l- The l ethoxyethinyl-2-allyl-2,4b-dimethyl-7-ethylene dioxy 1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene-1-ol-4-one used as starting material in Example 22 hereinabove can be prepared from 2,4b-dimethyl-7- ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,10a-dodecahydrophenanthrene-l,4-dione (the preparation of which is described hereinabove) in accordance with the following procedure:

To a solution containing 4.0 g. of 2,4b-dirnethyl-7- ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,10a-dodecahydrophenanthrene-1,4-dione dissolved in 50 ml. of anhydrous benzene is added 20 ml. of a 1 M solution of potassium t-butoxide in t-butyl alcohol and 3 ml. of allyl iodide. The resulting solution is allowed to stand at room temperature for a period of approximately one hour, at the end of which time ice water is added to the reaction mixture. The aqueous mixture is extracted with ether, and the ethereal extract is evaporated to dryness. The residual crystalline material is dissolved in benzene-petroleum ether, and the solution is chromatographed on acidashed alumina, and the chromatogram is eluted with e er-petroleum ether. The solvents are evaporated from this ether-petroleum ether eluate to give 2-allyl2,4b-dimethyl- 7-ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene-l,4-dione.

To an ethereal solution of 2.2 molar equivalents of ethoxyacetylene magnesium bromide was added 37.5 g. of 2-allyl-2,4b-dimethyl 7 ethylenedioxy-l,2,3,4,4a,4b,5, 6,7,8,l0,10a-dodecahydrophenanthrene-1,4-dione in 950 ml. of benzene. The reaction mixture wase stirred for 2/2 hours at room temperature. It was then poured onto ice water and extracted with ether. The extract was washed with water, dried, and concentrated in vacuo. The non-crystalline residue was chromatographed on 1.6 kg. of alkaline alumina. With petroleum ether-ether eluates there was eluted first l-ethoxyethinyl-2-allyl-2,4bdimethyl 7 ethylenedioxy-l,2,3,4-,4a,4b,5,6,7,8,10,l0adodecahydrophenanthrene-1-ol-4-one, melting at 83.5- 85.0 C. after recrystallization from ether-petroleum ether. Further elution gave a stereoisomer of this substance, M.P. 159-160 C.

Various changes and modifications may be made in carrying out the present invention without departing from the spirit and scope thereof. Insofar as these changes and modifications are within the purview of the annexed claims, they are to be considered as part of this invention.

We claim:

1. 1-carboxymethylene-2-methallyl 2,4b dimethyl-4- hydroxy 7 ethylenedioxy-l,2,3,4,4a,4b,5,6,7,8,10,10adodecahydrophenanthrene.

2. l-carboxymethylene 2 allyl-2,4b-dimethyl-4-hydroxy-7-ethylenedioxy l,2,3,4,4a,4b,5,6,7,8,l0,10a dodecahydrophenanthrene.

3. l-carboxymethylene 2 methallyl-2,4b-dimethyl-4- hydroxy-7-keto-1,2,3,4,4a,4b,5,6,7,9,10,10a dodecahydrophenanthrene.

4. A compound having the following formula:

wherein Z stands for lower alkylenedioxy; R is selected from the group consisting of hydrogen and lower alkyl;

=CHCOOR and Y is selected from the group consisting of allyl and methallyl.

References Cited in the file of this patent 

4. A COMPOUND HAVING THE FOLLOWING FORMULA: 